BioPAX pathway converted from "Transcriptional Regulation by TP53" in the Reactome database.Transcriptional Regulation by TP53The tumor suppressor TP53 (encoded by the gene p53) is a transcription factor. Under stress conditions, it recognizes specific responsive DNA elements and thus regulates the transcription of many genes involved in a variety of cellular processes, such as cellular metabolism, survival, senescence, apoptosis and DNA damage response. Because of its critical function, p53 is frequently mutated in around 50% of all malignant tumors. For a recent review, please refer to Vousden and Prives 2009 and Kruiswijk et al. 2015.Authored: Orlic-Milacic, Marija, 2015-10-14Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2015-10-14TP53 Regulates Metabolic GenesWhile the p53 tumor suppressor protein (TP53) is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism to prevent tumor development. TP53 regulates transcription of many genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration.<p>TP53 stimulates transcription of TIGAR, a D-fructose 2,6-bisphosphatase. TIGAR activity decreases glycolytic rate and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006). TP53 may also negatively regulate the rate of glycolysis by inhibiting the expression of glucose transporters GLUT1, GLUT3 and GLUT4 (Kondoh et al. 2005, Schwartzenberg-Bar-Yoseph et al. 2004, Kawauchi et al. 2008).<p>TP53 negatively regulates several key points in PI3K/AKT signaling and downstream mTOR signaling, decreasing the rate of protein synthesis and, hence, cellular growth. TP53 directly stimulates transcription of the tumor suppressor PTEN, which acts to inhibit PI3K-mediated activation of AKT (Stambolic et al. 2001). TP53 stimulates transcription of sestrin genes, SESN1, SESN2, and SESN3 (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007). One of sestrin functions may be to reduce and reactivate overoxidized peroxiredoxin PRDX1, thereby reducing ROS levels (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009). Another function of sestrins is to bind the activated AMPK complex and protect it from AKT-mediated inactivation. By enhancing AMPK activity, sestrins negatively regulate mTOR signaling (Budanov and Karin 2008, Cam et al. 2014). The expression of DDIT4 (REDD1), another negative regulator of mTOR signaling, is directly stimulated by TP63 and TP53. DDIT4 prevents AKT-mediated inactivation of TSC1:TSC2 complex, thus inhibiting mTOR cascade (Cam et al. 2014, Ellisen et al. 2002, DeYoung et al. 2008). TP53 may also be involved, directly or indirectly, in regulation of expression of other participants of PI3K/AKT/mTOR signaling, such as PIK3CA (Singh et al. 2002), TSC2 and AMPKB (Feng et al. 2007). <p>TP53 regulates mitochondrial metabolism through several routes. TP53 stimulates transcription of SCO2 gene, which encodes a mitochondrial cytochrome c oxidase assembly protein (Matoba et al. 2006). TP53 stimulates transcription of RRM2B gene, which encodes a subunit of the ribonucleotide reductase complex, responsible for the conversion of ribonucleotides to deoxyribonucleotides and essential for the maintenance of mitochondrial DNA content in the cell (Tanaka et al. 2000, Bourdon et al. 2007, Kulawiec et al. 2009). TP53 also transactivates mitochondrial transcription factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance (Park et al. 2009). Finally, TP53 stimulates transcription of the mitochondrial glutaminase GLS2, leading to increased mitochondrial respiration rate and reduced ROS levels (Hu et al. 2010). <p>The great majority of tumor cells generate energy through aerobic glycolysis, rather than the much more efficient aerobic mitochondrial respiration, and this metabolic change is known as the Warburg effect (Warburg 1956). Since the majority of tumor cells have impaired TP53 function, and TP53 regulates a number of genes involved in glycolysis and mitochondrial respiration, it is likely that TP53 inactivation plays an important role in the metabolic derangement of cancer cells such as the Warburg effect and the concomitant increased tumorigenicity (reviewed by Feng and Levine 2010). On the other hand, some mutations of TP53 in Li-Fraumeni syndrome may result in the retention of its wild-type metabolic activities while losing cell cycle and apoptosis functions (Wang et al. 2013). Consistent with such human data, some mutations of p53, unlike p53 null state, retain the ability to regulate energy metabolism while being inactive in regulating its classic gene targets involved in cell cycle, apoptosis and senescence. Retention of metabolic and antioxidant functions of p53 protects p53 mutant mice from early onset tumorigenesis (Li et al. 2012). Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23LEFT-TO-RIGHTTP53 binds the TIGAR geneTIGAR gene possesses two TP53 (p53) binding sites, one upstream of the first exon and another within the first intron. TP53 can bind both sites, with a higher affinity for the intronic site (Bensaad et al. 2006).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23TP53 TetramerReactome DB_ID: 3209194nucleoplasmGENE ONTOLOGYGO:0005654TP53p53 proteinP53_HUMANCellular tumor antigen p53Tumor suppressor p53Phosphoprotein p53Antigen NY-CO-13Reactome DB_ID: 69488UniProt:P04637 TP53TP53P53FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).SUBUNIT Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, BANP, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561).SUBUNIT (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.TISSUE SPECIFICITY Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.INDUCTION Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.DOMAIN The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.PTM Acetylated. Acetylation of Lys-382 by CREBBP enhances transcriptional activity. Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner.PTM Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated on Ser-15 upon ultraviolet irradiation; which is enhanced by interaction with BANP. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).PTM Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.PTM May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.PTM Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity).PTM Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).PTM Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.DISEASE TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.SIMILARITY Belongs to the p53 family.Homo sapiensNCBI Taxonomy9606UniProtP046371EQUAL393EQUALReactome Database ID Release 7569488Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69488ReactomeR-HSA-694881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-69488.1Reactomehttp://www.reactome.org4Reactome Database ID Release 753209194Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3209194ReactomeR-HSA-32091941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3209194.1TIGAR GeneReactome DB_ID: 5628852ENSEMBL:ENSG00000078237 TIGARTIGARC12orf5ENSEMBLENSG00000078237Reactome Database ID Release 755628852Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628852ReactomeR-HSA-56288521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5628852.1TP53 Tetramer:TIGAR GeneReactome DB_ID: 562890011Reactome Database ID Release 755628900Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628900ReactomeR-HSA-56289001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5628900.1Reactome Database ID Release 755628899Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628899ReactomeR-HSA-56288994Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5628899.416839880Pubmed2006TIGAR, a p53-inducible regulator of glycolysis and apoptosisBensaad, KarimTsuruta, AtsushiSelak, Mary AVidal, M Nieves CalvoNakano, KatsunoriBartrons, RamonGottlieb, EyalVousden, Karen HCell 126:107-20LEFT-TO-RIGHTTP53 stimulates TIGAR expressionTIGAR was first identified as a TP53 target through high-throughput gene expression profiling (Jen and Cheung 2005). TP53 stimulates TIGAR transcription, although TIGAR can be regulated through TP53-independent mechanisms, including TP53 family members TP63 (p63) and TP73 (p73). TIGAR is induced by TP53 under low stress levels and decreases under high stress levels (Bensaad et al. 2006). TIGAR functions as a fructose-2,6-bisphosphatase, thereby lowering glycolytic flux and promoting antioxidant functions. By protecting cells from oxidative stress, TIGAR may mediate some of the tumor suppressor activity of p53 but could also contribute to tumorigenesis. (Bensaad, 2006, Lee et al. 2014). Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23TIGARFructose-2,6-bisphosphatase TIGARC12orf5TP53-induced glycolysis and apoptosis regulatorReactome DB_ID: 5628829cytosolGENE ONTOLOGYGO:0005829UniProt:Q9NQ88 TIGARTIGARC12orf5FUNCTION Fructose-bisphosphatase hydrolyzing fructose-2,6-bisphosphate as well as fructose-1,6-bisphosphate (PubMed:19015259). Acts as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate in a p53/TP53-dependent manner, resulting in the pentose phosphate pathway (PPP) activation and NADPH production (PubMed:16839880, PubMed:22887998). Contributes to the generation of reduced glutathione to cause a decrease in intracellular reactive oxygen species (ROS) content, correlating with its ability to protect cells from oxidative or metabolic stress-induced cell death (PubMed:16839880, PubMed:19713938, PubMed:23726973, PubMed:22887998, PubMed:23817040). Plays a role in promoting protection against cell death during hypoxia by decreasing mitochondria ROS levels in a HK2-dependent manner through a mechanism that is independent of its fructose-bisphosphatase activity (PubMed:23185017). In response to cardiac damage stress, mediates p53-induced inhibition of myocyte mitophagy through ROS levels reduction and the subsequent inactivation of BNIP3. Reduced mitophagy results in an enhanced apoptotic myocyte cell death, and exacerbates cardiac damage (By similarity). Plays a role in adult intestinal regeneration; contributes to the growth, proliferation and survival of intestinal crypts following tissue ablation (PubMed:23726973). Plays a neuroprotective role against ischemic brain damage by enhancing PPP flux and preserving mitochondria functions (By similarity). Protects glioma cells from hypoxia- and ROS-induced cell death by inhibiting glycolysis and activating mitochondrial energy metabolism and oxygen consumption in a TKTL1-dependent and p53/TP53-independent manner (PubMed:22887998). Plays a role in cancer cell survival by promoting DNA repair through activating PPP flux in a CDK5-ATM-dependent signaling pathway during hypoxia and/or genome stress-induced DNA damage responses (PubMed:25928429). Involved in intestinal tumor progression (PubMed:23726973).SUBUNIT Interacts with HK2; the interaction increases hexokinase HK2 activity in a hypoxia- and HIF1A-dependent manner, resulting in the regulation of mitochondrial membrane potential, thus increasing NADPH production and decreasing intracellular ROS levels (PubMed:23185017).TISSUE SPECIFICITY Expressed in the brain (PubMed:22887998). Expressed in breast tumors (PubMed:21820150). Expressed in glioblastomas (PubMed:22887998).INDUCTION Up-regulated by p53/TP53 (at protein level) (PubMed:16839880). Rapidly up-regulated by p53/TP53 (PubMed:16140933, PubMed:16839880, PubMed:19713938). Up-regulated in glioma cell line in a p53/TP53-independent manner (PubMed:22887998).SIMILARITY Belongs to the phosphoglycerate mutase family.CAUTION Not expected to have any kinase activity.UniProtQ9NQ881EQUAL270EQUALReactome Database ID Release 755628829Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628829ReactomeR-HSA-56288291Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5628829.1Reactome Database ID Release 755628901Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628901ReactomeR-HSA-56289014Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5628901.416140933Pubmed2005Identification of novel p53 target genes in ionizing radiation responseJen, Kuang-YuCheung, Vivian GCancer Res. 65:7666-7326652033Pubmed2016Novel therapeutic interventions for p53-altered tumors through manipulation of its family members, p63 and p73Venkatanarayan, AvinashnarayanRaulji, PayalNorton, WilliamFlores, Elsa RCell Cycle 15:164-7124383451Pubmed2014TIGAR, TIGAR, burning brightLee, PearlVousden, Karen HCheung, Eric CCancer Metab 2:1ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 755628903Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628903ReactomeR-HSA-56289031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5628903.1LEFT-TO-RIGHT3.1.3.46TIGAR converts D-fructose-2,6-bisphosphate to D-fructose 6-phosphateTIGAR shares similarity with PGMs (phosphoglycerate mutases), especially PFK2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). TIGAR possesses only the bisphosphatase domain and converts D-fructose 2,6-bisphosphate into D-fructose 6-phosphate (Bensaad et al. 2006). Reduction of fructose 2,6-bisphosphate levels correlates with decrease in glycolytic rates, which makes cells more sensitive to apoptotic stimuli (Vander Heiden et al. 2001). Alternatively, fructose 6-phosphate can be isomerized to glucose 6-phosphate, which is diverted to the pentose phosphate pathway, which can have an anti-apoptotic effect (Boada et al. 2000, Perez et al. 2000). In the pentose phosphate pathway, oxidized glutathione is reduced, and this reduced glutathione can then be used by glutathione peroxidase to remove hydrogen peroxide, thereby protecting cells from the oxidative stress (Kletzien et al. 1994, Fico et al. 2004, Tian et al. 1999). Indeed, expression of TIGAR increases reduced glutathione to oxidized glutathione ratio and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006, Lee et al. 2014). Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23H2OwaterReactome DB_ID: 29356water [ChEBI:15377]waterChEBICHEBI:15377Reactome Database ID Release 7529356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29356ReactomeR-ALL-293565Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29356.5COMPOUNDC00001additional informationMIMI:0361D-Fructose 2,6-bisphosphatebeta-D-fructofuranose 2,6-bisphosphateReactome DB_ID: 30533beta-D-fructofuranose 2,6-bisphosphate [ChEBI:28602]beta-D-fructofuranose 2,6-bisphosphateChEBICHEBI:28602Reactome Database ID Release 7530533Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=30533ReactomeR-ALL-305333Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-30533.3COMPOUNDC00665Fru(6)PD-Fructose 6-phosphateketo-D-fructose 6-phosphateD-Fructose 6-phosphoric acidNeuberg esterD-fructose 6-phosphate(2-)Reactome DB_ID: 29512beta-D-fructofuranose 6-phosphate(2-) [ChEBI:57634]beta-D-fructofuranose 6-phosphate(2-)beta-D-fructofuranose 6-phosphate dianion6-O-phosphonato-beta-D-fructofuranoseChEBICHEBI:57634Reactome Database ID Release 7529512Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29512ReactomeR-ALL-295124Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29512.4COMPOUNDC00085PiOrthophosphatehydrogenphosphatePhosphateInorganic PhosphateReactome DB_ID: 29372hydrogenphosphate [ChEBI:43474]hydrogenphosphatehydrogen phosphatephosphate[PO3(OH)](2-)INORGANIC PHOSPHATE GROUPHYDROGENPHOSPHATE IONHPO4(2-)[P(OH)O3](2-)ChEBICHEBI:43474Reactome Database ID Release 7529372Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29372ReactomeR-ALL-293724Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29372.4COMPOUNDC00009ACTIVATIONGENE ONTOLOGYGO:0004331gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 755628908Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628908Reactome Database ID Release 755628905Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5628905ReactomeR-HSA-56289055Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5628905.58119488Pubmed1994Glucose-6-phosphate dehydrogenase: a "housekeeping" enzyme subject to tissue-specific regulation by hormones, nutrients, and oxidant stressKletzien, R FHarris, P KFoellmi, L AFASEB J. 8:174-8111486029Pubmed2001Growth factors can influence cell growth and survival through effects on glucose metabolismVander Heiden, M GPlas, D RRathmell, J CFox, C JHarris, M HThompson, C BMol. Cell. Biol. 21:5899-91211034341Pubmed2000Cells overexpressing fructose-2,6-bisphosphatase showed enhanced pentose phosphate pathway flux and resistance to oxidative stressBoada, JRoig, TPerez, XGámez, ABartrons, RCascante, MBermúdez, JFEBS Lett. 480:261-411029283Pubmed2000Overexpression of fructose 2,6-bisphosphatase decreases glycolysis and delays cell cycle progressionPerez, J XRoig, TManzano, ADalmau, MBoada, JVentura, FRosa, J LBermudez, JBartrons, RAm. J. Physiol., Cell Physiol. 279:C1359-6515044966Pubmed2004Glucose-6-phosphate dehydrogenase plays a crucial role in protection from redox-stress-induced apoptosisFico, APaglialunga, FCigliano, LAbrescia, PVerde, PMartini, GIaccarino, IFilosa, SCell Death Differ. 11:823-3110329961Pubmed1999Importance of glucose-6-phosphate dehydrogenase activity in cell deathTian, W NBraunstein, L DApse, KPang, JRose, MTian, XStanton, R CAm. J. Physiol. 276:C1121-31LEFT-TO-RIGHT5.3.1.9D-fructose 6-phosphate <=> alpha-D-Glucose 6-phosphateThe reversible isomerization of fructose-6-phosphate to form glucose-6-phosphate is catalyzed by cytosolic phosphoglucose isomerase (Noltman 1972; Xu and Beutler 1994; Tsuboi et al. 1958).Authored: Schmidt, EE, 2003-02-05 00:00:00Reviewed: D'Eustachio, P, 2003-06-25 00:00:00Reviewed: Harris, RA, 2008-09-10 18:47:12Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: D'Eustachio, P, 2008-09-10 19:02:07G6Palpha-D-glucose 6-phosphatealpha-D-glucose 6-phosphate(2-)Reactome DB_ID: 30537alpha-D-glucose 6-phosphate(2-) [ChEBI:58225]alpha-D-glucose 6-phosphate(2-)alpha-D-glucopyranose 6-phosphatealpha-D-glucose 6-phosphate dianionalpha-D-glucose 6-phosphate6-O-phosphonato-alpha-D-glucopyranoseChEBICHEBI:58225Reactome Database ID Release 7530537Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=30537ReactomeR-ALL-305374Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-30537.4COMPOUNDC00668ACTIVATIONGPI dimerglucose 6-phosphate isomerase dimerReactome DB_ID: 70469GPIGlucose-6-phosphate isomerase Phosphoglucose isomerasePGIPhosphohexose isomerasePHINeuroleukinNLKSperm antigen-36SA-36Reactome DB_ID: 70468UniProt:P06744 GPIGPIFUNCTION In the cytoplasm, catalyzes the conversion of glucose-6-phosphate to fructose-6-phosphate, the second step in glycolysis, and the reverse reaction during gluconeogenesis (PubMed:28803808). Besides it's role as a glycolytic enzyme, also acts as a secreted cytokine: acts as an angiogenic factor (AMF) that stimulates endothelial cell motility (PubMed:11437381). Acts as a neurotrophic factor, neuroleukin, for spinal and sensory neurons (PubMed:3352745, PubMed:11004567). It is secreted by lectin-stimulated T-cells and induces immunoglobulin secretion (PubMed:3352745, PubMed:11004567).ACTIVITY REGULATION Strongly inhibited by erythrose 4-phosphate.PATHWAY Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 2/4.SUBUNIT Homodimer; in the catalytically active form (PubMed:11371164, PubMed:12054796, PubMed:12777791). Monomer in the secreted form (PubMed:11371164, PubMed:12054796, PubMed:12777791).PTM Phosphorylation at Ser-185 by CK2 has been shown to decrease enzymatic activity and may contribute to secretion by a non-classical secretory pathway.PTM ISGylated.SIMILARITY Belongs to the GPI family.UniProtP067442EQUAL558EQUALReactome Database ID Release 7570468Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70468ReactomeR-HSA-704681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70468.12Reactome Database ID Release 7570469Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70469ReactomeR-HSA-704692Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70469.2GENE ONTOLOGYGO:0004347Reactome Database ID Release 7570470Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70470Reactome Database ID Release 7570475Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70475ReactomeR-HSA-704753Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70475.313538944Pubmed1958Enzymes of the human erythrocyte. IV. Phosphoglucose isomerase, purification and properties.Tsuboi, KKEstrada, JHudson, PBJ Biol Chem 231:19-297989588Pubmed1994The characterization of gene mutations for human glucose phosphate isomerase deficiency associated with chronic hemolytic anemiaXu, WBeutler, ErnestJ Clin Invest 94:2326-90121227022ISBN1972Aldose-ketose isomerasesNoltmann, EAThe Enzymes, 3rd ed (Book): 271-354LEFT-TO-RIGHT1.1.1.49alpha-D-glucose 6-phosphate + NADP+ => D-glucono-1,5-lactone 6-phosphate + NADPH + H+Cytosolic glucose-6-phosphate dehydrogenase (G6PD) catalyzes the reaction of glucose 6-phosphate and NADP+ to form D-glucono-1,5-lactone 6-phosphate and NADPH + H+. This constitutes the first committed step of the pentose phosphate pathway and it is critical to the maintenance of NAPDH pool and redox homeostasis. For this reason, anti-cancer therapies are making this step as a prominent target in cancer therapy (Zhang et al. 2014). The reaction is inhibited by high ADP/AMP concentration, and by high NAPDH concentration. Biochemical studies indicate that both G6PD dimers and tetramers are catalytically active and present under physiological conditions in vivo (Au et al. 2000). Mutations that reduce the catalytic efficiency of G6PD are remarkably common in human populations; these appear to have a protective effect against malaria (e.g., Luzzatto and Afolayan 1968).Authored: D'Eustachio, P, 2003-06-25 00:00:00Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: D'Eustachio, P, 2010-01-24TPNNADP+NADPNADP(+)Nicotinamide adenine dinucleotide phosphatebeta-Nicotinamide adenine dinucleotide phosphateTriphosphopyridine nucleotideReactome DB_ID: 29366NADP(+) [ChEBI:18009]NADP(+)ChEBICHEBI:18009Reactome Database ID Release 7529366Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29366ReactomeR-ALL-293663Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29366.3COMPOUNDC00006TPNHNADPHReactome DB_ID: 29364NADPH [ChEBI:16474]NADPHTPNHChEBICHEBI:16474Reactome Database ID Release 7529364Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29364ReactomeR-ALL-293642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29364.2COMPOUNDC000056-Phospho-D-glucono-1,5-lactoneD-Glucono-1,5-lactone 6-phosphate6-O-phosphono-D-glucono-1,5-lactoneReactome DB_ID: 314676-O-phosphono-D-glucono-1,5-lactone [ChEBI:16938]6-O-phosphono-D-glucono-1,5-lactoneChEBICHEBI:16938Reactome Database ID Release 7531467Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=31467ReactomeR-ALL-314673Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-31467.3COMPOUNDC01236H+protonhydronReactome DB_ID: 70106hydron [ChEBI:15378]hydronChEBICHEBI:15378Reactome Database ID Release 7570106Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70106ReactomeR-ALL-701064Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-70106.4COMPOUNDC00080ACTIVATIONConverted from EntitySet in ReactomeG6PD dimer and tetramerReactome DB_ID: 464971G6PD dimerglucose-6-phosphate 1-dehydrogenase dimerReactome DB_ID: 703732G6PDGlucose-6-phosphate 1-dehydrogenase Reactome DB_ID: 70372UniProt:P11413 G6PDG6PDFUNCTION Cytosolic glucose-6-phosphate dehydrogenase that catalyzes the first and rate-limiting step of the oxidative branch within the pentose phosphate pathway/shunt, an alternative route to glycolysis for the dissimilation of carbohydrates and a major source of reducing power and metabolic intermediates for fatty acid and nucleic acid biosynthetic processes.PATHWAY Carbohydrate degradation; pentose phosphate pathway; D-ribulose 5-phosphate from D-glucose 6-phosphate (oxidative stage): step 1/3.SUBUNIT Homotetramer; dimer of dimers (PubMed:24769394, PubMed:10745013, PubMed:15858258). Interacts with SIRT2; the interaction is enhanced by H(2)O(2) treatment (PubMed:24769394).TISSUE SPECIFICITY Isoform Long is found in lymphoblasts, granulocytes and sperm.PTM Acetylated by ELP3 at Lys-403; acetylation inhibits its homodimerization and enzyme activity. Deacetylated by SIRT2 at Lys-403; deacetylation stimulates its enzyme activity.POLYMORPHISM The sequence shown is that of variant B, the most common variant.MISCELLANEOUS Binds two molecules of NADP. The first one is a cosubstrate (bound to the N-terminal domain), the second is bound to the C-terminal domain and functions as a structural element.SIMILARITY Belongs to the glucose-6-phosphate dehydrogenase family.UniProtP114132EQUAL515EQUALReactome Database ID Release 7570372Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70372ReactomeR-HSA-703721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70372.12Reactome Database ID Release 7570373Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70373ReactomeR-HSA-703731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70373.1G6PD tetramerglucose-6-phosphate 1-dehydrogenase tetramerReactome DB_ID: 7037544Reactome Database ID Release 7570375Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70375ReactomeR-HSA-703751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70375.1Reactome Database ID Release 75464971Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=464971ReactomeR-HSA-4649711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-464971.1GENE ONTOLOGYGO:0004345Reactome Database ID Release 7570374Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70374Reactome Database ID Release 7570377Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70377ReactomeR-HSA-703773Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70377.310745013Pubmed2000Human glucose-6-phosphate dehydrogenase: the crystal structure reveals a structural NADP(+) molecule and provides insights into enzyme deficiencyAu, SWGover, SLam, VMAdams, MJStructure 8:293-3035666113Pubmed1968Enzymic properties of different types of human erythrocyte glucose-6-phosphate dehydrogenase, with characterization of two new genetic variantsLuzzatto, LAfolayan, AJ Clin Invest 47:1833-4224066844Pubmed2014Glucose-6-phosphate dehydrogenase: a biomarker and potential therapeutic target for cancerZhang, ChunhuaZhang, ZhengZhu, YuechunQin, SuofuAnticancer Agents Med Chem 14:280-9LEFT-TO-RIGHT1.8.1.7glutathione (oxidized) + NADPH + H+ => 2 glutathione (reduced) + NADP+Cytosolic glutathione reductase catalyzes the reaction of glutathione (oxidized) and NADPH + H+ to form two molecules of glutathione (reduced) and NADP+ (Scott et al. 1963, Loos et al. 1976). Deficiency of glutathione reductase can cause hemolytic anemia.Authored: D'Eustachio, P, 2004-03-17 17:27:00Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: D'Eustachio, P, 2004-03-17 17:27:00Edited: Vastrik, I, 2005-04-29 06:26:51GSSGoxidized glutathioneglutathione disulfideReactome DB_ID: 111745glutathione disulfide [ChEBI:17858]glutathione disulfideChEBICHEBI:17858Reactome Database ID Release 75111745Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111745ReactomeR-ALL-1117453Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-111745.3COMPOUNDC00127GSHReduced glutathioneglutathione5-L-Glutamyl-L-cysteinylglycineN-(N-gamma-L-Glutamyl-L-cysteinyl)glycinegamma-L-Glutamyl-L-cysteinyl-glycineReactome DB_ID: 29450glutathione [ChEBI:16856]glutathioneChEBICHEBI:16856Reactome Database ID Release 7529450Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29450ReactomeR-ALL-294503Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29450.3COMPOUNDC000512ACTIVATION2xGSR-2:2xFADGSR-2:FAD dimerglutathione reductase holoenzymeReactome DB_ID: 71680GRGSR-2glutathione reductaseGSHR_HUMANGlutathione reductase, mitochondrial precursor GRaseGSR isoform 2Reactome DB_ID: 71679UniProt:P00390-2 GSRGSRGLURGRD1FUNCTION Maintains high levels of reduced glutathione in the cytosol.SUBUNIT Homodimer; disulfide-linked.DOMAIN Each subunit can be divided into 4 domains that are consecutive along the polypeptide chain. Domains 1 and 2 bind FAD and NADPH, respectively. Domain 4 forms the interface.MISCELLANEOUS The active site is a redox-active disulfide bond.SIMILARITY Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.UniProt IsoformP00390-244EQUAL522EQUALReactome Database ID Release 7571679Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71679ReactomeR-HSA-716791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-71679.12FADFlavin adenine dinucleotideReactome DB_ID: 29386FAD [ChEBI:16238]FADFlavin adenine dinucleotideChEBICHEBI:16238Reactome Database ID Release 7529386Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29386ReactomeR-ALL-293862Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29386.2COMPOUNDC000162Reactome Database ID Release 7571680Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71680ReactomeR-HSA-716802Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-71680.2GENE ONTOLOGYGO:0004362Reactome Database ID Release 7571681Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71681Reactome Database ID Release 7571682Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=71682ReactomeR-HSA-716823Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-71682.314086726Pubmed1963PURIFICATION AND PROPERTIES OF GLUTATHIONE REDUCTASE OF HUMAN ERYTHROCYTESSCOTT, E MDUNCAN, I WEKSTRAND, VJ. Biol. Chem. 238:3928-33947404Pubmed1976Familial deficiency of glutathione reductase in human blood cellsLoos, HRoos, DWeening, RHouwerzijl, JBlood 48:53-62LEFT-TO-RIGHT1.11.1.9GPX2 catalyzes 2 glutathione, reduced + H2O2 => glutathione, oxidized + 2 H2OGPX2 (located in the gastrointestinal tract, also called GSHPx-GI, GPX-GI, and GI-GPx), like glutathione peroxidase 1 (GPX1, ubiquitous), reduces one molecule of hydrogen peroxide (H2O2) with two molecules of glutathione to yield one molecule of oxidized glutathione (glutathione disulfide, GSSG) and two molecules of water (Chu et al. 1998).Authored: May, B, 2013-05-09Reviewed: Kavdia, Mahendra, 2013-11-01Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: May, B, 2013-05-092H2O2hydrogen peroxideReactome DB_ID: 29408hydrogen peroxide [ChEBI:16240]hydrogen peroxideChEBICHEBI:16240Reactome Database ID Release 7529408Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29408ReactomeR-ALL-294083Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29408.3COMPOUNDC000272ACTIVATIONGPX2 tetramerglutathione peroxidase tetramerReactome DB_ID: 2142735GPX2L-selenocysteine-residue-GPX2Glutathione peroxidase 2GPX2_HUMANReactome DB_ID: 2142687UniProt:P18283 GPX2GPX2FUNCTION Could play a major role in protecting mammals from the toxicity of ingested organic hydroperoxides. Tert-butyl hydroperoxide, cumene hydroperoxide and linoleic acid hydroperoxide but not phosphatidycholine hydroperoxide, can act as acceptors.SUBUNIT Homotetramer.TISSUE SPECIFICITY Mostly in liver and gastrointestinal tract, not found in heart or kidney.SIMILARITY Belongs to the glutathione peroxidase family.UniProtP1828340EQUALL-selenocysteine residueMODMOD:000311EQUAL190EQUALReactome Database ID Release 752142687Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142687ReactomeR-HSA-21426872Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142687.24Reactome Database ID Release 752142735Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2142735ReactomeR-HSA-21427351Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2142735.1GENE ONTOLOGYGO:0004602Reactome Database ID Release 753341295Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341295Reactome Database ID Release 753341277Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341277ReactomeR-HSA-33412772Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341277.28428933Pubmed1993Expression, characterization, and tissue distribution of a new cellular selenium-dependent glutathione peroxidase, GSHPx-GIChu, FFDoroshow, JHEsworthy, RSJ Biol Chem 268:2571-6LEFT-TO-RIGHTTP53 binds the PTEN promoterPTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) binds to the p53-binding site at the PTEN promoter level (Stambolic et al. 2001).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Reviewed: Salmena, Leonardo, 2016-08-11Reviewed: Carracedo, Arkaitz, 2016-08-11Reviewed: Leslie, Nicholas, 2016-09-30Reviewed: Kriplani, Nisha, 2016-09-30Edited: Orlic-Milacic, Marija, 2014-12-23PTEN geneReactome DB_ID: 5632949ENSEMBL:ENSG00000171862 PTENPTENMMAC1TEP1ENSEMBLENSG00000171862Reactome Database ID Release 755632949Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632949ReactomeR-HSA-56329492Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632949.2TP53 Tetramer:PTEN GeneReactome DB_ID: 563294111Reactome Database ID Release 755632941Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632941ReactomeR-HSA-56329411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632941.1Reactome Database ID Release 755632939Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632939ReactomeR-HSA-56329396Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632939.611545734Pubmed2001Regulation of PTEN transcription by p53Stambolic, VMacPherson, DSas, DLin, YSnow, BJang, YBenchimol, SMak, T WMol. Cell 8:317-25LEFT-TO-RIGHTPTEN gene transcription is stimulated by TP53PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) stimulates PTEN transcription (Stambolic et al. 2000, Singh et al. 2002). PTEN, acting as a negative regulator of PI3K/AKT signaling, affects cell survival, cell cycling, proliferation and migration. PTEN regulates TP53 stability by inhibiting AKT-mediated activation of TP53 ubiquitin ligase MDM2, and thus enhances TP53 transcriptional activity and its own transcriptional activation by TP53. Beside their cross-regulation, PTEN and TP53 can interact and cooperate to regulate survival or apoptotic phenomena (Stambolic et al. 2000, Singh et al. 2002, Nakanishi et al. 2014).<br>In response to UV induced DNA damage, PTEN transcription is stimulated by binding of the transcription factor EGR1 to the promoter region of PTEN (Virolle et al. 2001).<br>PTEN transcription is also stimulated by binding of the activated nuclear receptor PPARG (PPARgamma) to peroxisome proliferator response elements (PPREs) in the promoter of the PTEN gene (Patel et al. 2001), binding of the ATF2 transcription factor, activated by stress kinases of the p38 MAPK family, to ATF response elements in the PTEN gene promoter (Shen et al. 2006) and by the transcription factor MAF1 (Li et al. 2016).<br>NR2E1 (TLX) associated with transcription repressors binds the evolutionarily conserved TLX consensus site in the PTEN promoter. NR2E1 inhibits PTEN transcription by associating with various transcriptional repressors, probably in a cell type or tissue specific manner. PTEN transcription is inhibited when NR2E1 forms a complex with ATN1 (atrophin-1) (Zhang et al. 2006, Yokoyama et al. 2008), KDM1A (LSD1) histone methyltransferase containing CoREST complex (Yokoyama et al. 2008), or histone deacetylases HDAC3, HDAC5 or HDAC7 (Sun et al. 2007).<br>Binding of the transcriptional repressor SNAI1 (Snail1) to the PTEN promoter represses PTEN transcription. SNAI1-mediated repression of PTEN transcription may require phosphorylation of SNAI1 on serine residue S246. Binding of SNAI1 to the PTEN promoter increases in response to ionizing radiation and is implicated in SNAI1-mediated resistance to gamma-radiation induced apoptosis (Escriva et al. 2008). Binding of another Slug/Snail family member SNAI2 (SLUG) to the PTEN gene promoter also represses PTEN transcription (Uygur et al. 2015).<br>Binding of JUN to the AP-1 element in the PTEN gene promoter (Hettinger et al. 2007) inhibits PTEN transcription. JUN partner FOS is not needed for JUN-mediated downregulation of PTEN (Vasudevan et al. 2007).<br>Binding of the transcription factor SALL4 to the PTEN gene promoter (Yang et al. 2008) and SALL4-medaited recruitment of the transcriptional repressor complex NuRD (Lu et al. 2009, Gao et al. 2013), containing histone deacetylases HDAC1 and HDAC2, inhibits the PTEN gene transcription. SALL4-mediated recruitment of DNA methyltransferases (DNMTs) is also implicated in transcriptional repression of PTEN (Yang et al. 2012).<br>Binding of the transcription factor MECOM (EVI1) to the PTEN gene promoter and MECOM-mediated recruitment of polycomb repressor complexes containing BMI1 (supposedly PRC1.4), and EZH2 (PRC2) leads to repression of PTEN transcription (Song et al. 2009, Yoshimi et al. 2011).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23PTEN mRNAReactome DB_ID: 2318746ENSEMBL:ENST00000371953 PTENPTENENSEMBLENST000003719531EQUAL9027EQUALReactome Database ID Release 752318746Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318746ReactomeR-HSA-23187461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318746.1Reactome Database ID Release 755632993Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632993ReactomeR-HSA-56329938Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632993.824718924Pubmed2014The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review)Nakanishi, AtsukoKitagishi, YasukoOgura, YasunoriMatsuda, SatoruInt. J. Oncol. 44:1813-911959846Pubmed2002p53 regulates cell survival by inhibiting PIK3CA in squamous cell carcinomasSingh, BReddy, Pabbathi GGoberdhan, AndyWalsh, ChristineDao, SuNgai, IvanChou, Ting ChaoO-Charoenrat, PornchaiLevine, Arnold JRao, Pulivarthi HStoffel, ArchontoulaGenes Dev. 16:984-93ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 755632990Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632990ReactomeR-HSA-56329901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632990.1LEFT-TO-RIGHTmiR-26A microRNAs bind PTEN mRNAMIR26A microRNAs, miR-26A1 and miR-26A2, transcribed from genes on chromosome 3 and 12, respectively, bind PTEN mRNA (Huse et al. 2009).<br><br>The MIR26A2 locus is frequently amplified in glioma tumors that retain one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to down-regulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and negatively correlates with the loss of heterozygosity at the PTEN locus in a mouse PTEN +/- glioma model, based on monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).Authored: Orlic-Milacic, M, 2012-07-18Reviewed: Thorpe, Lauren, 2012-08-13Reviewed: Yuzugullu, Haluk, 2012-08-13Reviewed: Zhao, Jean J, 2012-08-13Reviewed: Leslie, Nicholas, 2016-09-30Reviewed: Kriplani, Nisha, 2016-09-30Reviewed: Carracedo, Arkaitz, 2016-08-11Reviewed: Salmena, Leonardo, 2016-08-11Edited: Matthews, L, 2012-08-03Converted from EntitySet in ReactomemiR-26A RISCmiR-26A-induced Silencing ComplexReactome DB_ID: 2318737miR-26A Endonucleolytic RISCReactome DB_ID: 2318744MOV10Putative helicase MOV-10MOV10_HUMANReactome DB_ID: 427772UniProt:Q9HCE1 MOV10MOV10KIAA1631FUNCTION 5' to 3' RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3' UTRs (PubMed:24726324). Required for microRNA (miRNA)-mediated gene silencing by the RNA-induced silencing complex (RISC). Required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC (PubMed:16289642, PubMed:17507929, PubMed:22791714). In cooperation with FMR1, regulates miRNA-mediated translational repression by AGO2 (PubMed:25464849). Restricts retrotransposition of long interspersed element-1 (LINE-1) in cooperation with TUT4 and TUT7 counteracting the RNA chaperonne activity of L1RE1 (PubMed:30122351, PubMed:23093941). Facilitates LINE-1 uridylation by TUT4 and TUT7 (PubMed:30122351). Required for embryonic viability and for normal central nervous system development and function. Plays two critical roles in early brain development: suppresses retroelements in the nucleus by directly inhibiting cDNA synthesis, while regulates cytoskeletal mRNAs to influence neurite outgrowth in the cytosol (By similarity). May function as a messenger ribonucleoprotein (mRNP) clearance factor (PubMed:24726324). Exhibits antiviral activity against dengue virus (DENV) (PubMed:27974568).FUNCTION (Microbial infection) Required for RNA-directed transcription and replication of the human hepatitis delta virus (HDV). Interacts with small capped HDV RNAs derived from genomic hairpin structures that mark the initiation sites of RNA-dependent HDV RNA transcription.SUBUNIT Interacts with DICER1, AGO2, TARBP2, EIF6 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929). Interacts with APOBEC3G in an RNA-dependent manner. Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with both protein products of LIRE1, ORF1p and ORF2p (PubMed:23093941). Interacts with TUT4 and, to a lesser extent, TUT7; the interactions are RNA-dependent (PubMed:30122351). Interacts with AGO2, TNRC6B and UPF1; the interactions are direct and RNA-dependent (PubMed:24726324). Interacts with FMR1; this interaction is direct, occurs in an RNA-dependent manner on polysomes and induces association of MOV10 with RNAs (PubMed:25464849). Interacts with SHFL; the interaction increases in presence of RNA (PubMed:27974568).SUBUNIT (Microbial infection) Interacts with the human hepatitis delta virus (HDV) antigen HDAg.SIMILARITY Belongs to the DNA2/NAM7 helicase family. SDE3 subfamily.UniProtQ9HCE11EQUAL1003EQUALReactome Database ID Release 75427772Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427772ReactomeR-HSA-4277721Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427772.11miR-26A Endonucleolytic Minimal RISCArgonaute2: miR-26A (single-stranded)Reactome DB_ID: 2318741AGO2EIF2C2Argonaute-2Reactome DB_ID: 209723UniProt:Q9UKV8 AGO2AGO2EIF2C2FUNCTION Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF-alpha) mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions.ACTIVITY REGULATION Inhibited by EDTA.SUBUNIT Interacts with DICER1 through its Piwi domain and with TARBP2 during assembly of the RNA-induced silencing complex (RISC). Together, DICER1, AGO2 and TARBP2 constitute the trimeric RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC). Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Note however that the term RISC has also been used to describe the trimeric RLC/miRLC. The formation of RISC complexes containing siRNAs rather than miRNAs appears to occur independently of DICER1. Interacts with AGO1. Also interacts with DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, ELAVL, FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, PABPC1, PRMT5, P4HA1, P4HB, RBM4, SART3, TNRC6A, TNRC6B, UPF1 and YBX1. Interacts with the P-body components DCP1A and XRN1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with RBM4; the interaction is modulated under stress-induced conditions, occurs under both cell proliferation and differentiation conditions and in an RNA- and phosphorylation-independent manner. Interacts with LIMD1, WTIP and AJUBA. Interacts with TRIM71; the interaction increases in presence of RNA (PubMed:23125361). Interacts with APOBEC3G in an RNA-dependent manner. Interacts with APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H. Interacts with DICER1, TARBP2, EIF6, MOV10 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929, PubMed:24726324). Interacts with FMR1 (PubMed:14703574). Interacts with ZFP36 (PubMed:15766526). Found in a complex, composed of AGO2, CHD7 and FAM172A (By similarity). Interacts with RC3H1; the interaction is RNA independent (PubMed:25697406). Interacts with SND1 (PubMed:14508492, PubMed:28546213). Interacts with SYT11 (By similarity). Interacts with CLNK (PubMed:26009488). Interacts with GARRE1 (PubMed:29395067).DOMAIN The Piwi domain may perform RNA cleavage by a mechanism similar to that of RNase H. However, while RNase H utilizes a triad of Asp-Asp-Glu (DDE) for metal ion coordination, this protein appears to utilize a triad of Asp-Asp-His (DDH).PTM Hydroxylated. 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity.SIMILARITY Belongs to the argonaute family. Ago subfamily.UniProtQ9UKV81EQUAL859EQUALReactome Database ID Release 75209723Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=209723ReactomeR-HSA-2097232Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-209723.21Converted from EntitySet in ReactomemiR-26AReactome DB_ID: 2318743MIR26A1miR-26A1microRNA 26A1Reactome DB_ID: 2318732miRBase:MI0000083 MIR26A1MIR26A1miRBaseMI000008310EQUAL31EQUALReactome Database ID Release 752318732Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318732ReactomeR-HSA-23187321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318732.1MIR26A2miR-26A2microRNA 26A2Reactome DB_ID: 2318734miRBase:MI0000750 MIR26A2MIR26A2miRBaseMI000075010EQUAL31EQUALReactome Database ID Release 752318734Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318734ReactomeR-HSA-23187341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318734.1Reactome Database ID Release 752318743Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318743ReactomeR-HSA-23187431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318743.11Reactome Database ID Release 752318741Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318741ReactomeR-HSA-23187411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318741.11Converted from EntitySet in ReactomeTNRC6 (GW182)Reactome DB_ID: 427775TNRC6ATrinucleotide repeat-containing gene 6A proteinTNR6A_HUMANReactome DB_ID: 427769UniProt:Q8NDV7 TNRC6ATNRC6ACAGH26KIAA1460TNRC6FUNCTION Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent repression of translation and for siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As a scaffolding protein, associates with argonaute proteins bound to partially complementary mRNAs, and can simultaneously recruit CCR4-NOT and PAN deadenylase complexes.SUBUNIT Interacts with AGO2 (PubMed:16284623, PubMed:16284622, PubMed:18690212, PubMed:19304925, PubMed:19324964, PubMed:19383768). Interacts with AGO1, AGO3 and AGO4 (PubMed:19324964, PubMed:19383768). Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex (PubMed:21981923). Interacts with ZC3H12A (PubMed:26134560). Interacts with SND1 (PubMed:28546213). Interacts with GARRE1 (PubMed:29395067).TISSUE SPECIFICITY Ubiquitous.INDUCTION By exogenous short interfering RNA (siRNA).MISCELLANEOUS Antibodies against TNRC6A are found in sera from patients with Sjoegren syndrome (SS), ataxia and sensor neuropathy diseases that developed autoantibodies against protein of the GWB structure. Autoantibodies were mapped to the GW-rich mid-part, the non-GW-rich region and the C-terminus of the protein.SIMILARITY Belongs to the GW182 family.UniProtQ8NDV71EQUAL1962EQUALReactome Database ID Release 75427769Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427769ReactomeR-HSA-4277691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427769.1TNRC6BTrinucleotide repeat-containing gene 6B proteinTNR6B_HUMANReactome DB_ID: 427777UniProt:Q9UPQ9 TNRC6BTNRC6BKIAA1093FUNCTION Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs) (PubMed:16289642, PubMed:19167051, PubMed:19304925, PubMed:32354837). Required for miRNA-dependent translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins (PubMed:16289642, PubMed:19167051, PubMed:19304925, PubMed:32354837). As scaffolding protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes (PubMed:21981923).SUBUNIT Interacts with AGO1, AGO2, AGO3 and AGO4 (PubMed:16289642, PubMed:18690212, PubMed:19167051, PubMed:19304925, PubMed:19383768). Interacts with CNOT1; the interaction mediates the association with the CCR4-NOT complex (PubMed:21981923, PubMed:21984185). Interacts with PAN3; the interaction mediates the association with the PAN complex (PubMed:21981923). Interacts with MOV10; the interaction is direct and RNA-dependent (PubMed:24726324).SIMILARITY Belongs to the GW182 family.UniProtQ9UPQ91EQUAL1833EQUALReactome Database ID Release 75427777Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427777ReactomeR-HSA-4277771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427777.1TNRC6CTrinucleotide repeat-containing gene 6C proteinTNR6C_HUMANReactome DB_ID: 427776UniProt:Q9HCJ0 TNRC6CTNRC6CKIAA1582FUNCTION Plays a role in RNA-mediated gene silencing by micro-RNAs (miRNAs). Required for miRNA-dependent translational repression of complementary mRNAs by argonaute family proteins. As scaffoldng protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes.SUBUNIT Interacts with one or more of the argonaute family proteins AGO1, AGO2, AGO3 and AGO4. Interacts with PABPC1 and EIF4G1. Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex. Interacts with PAN3; the interaction mediates the association with the PAN complex.DOMAIN The silencing domain, also known as C-terminal effector domain (CED), can act in autonomous repression, including both translational inhibition and mRNA degradation.SIMILARITY Belongs to the GW182 family.UniProtQ9HCJ01EQUAL1690EQUALReactome Database ID Release 75427776Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427776ReactomeR-HSA-4277761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427776.1Reactome Database ID Release 75427775Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=427775ReactomeR-HSA-4277751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-427775.11Reactome Database ID Release 752318744Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318744ReactomeR-HSA-23187441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318744.1miR-26A Nonendonucleolytic RISCReactome DB_ID: 231873811Argonaute1/3/4: miR-26AmiR-26A Nonendonucleolytic Minimal RISCReactome DB_ID: 2318739Converted from EntitySet in ReactomeNonendonucleolytic ArgonauteReactome DB_ID: 210613AGO1EIF2C1Argonaute-1Reactome DB_ID: 210616UniProt:Q9UL18 AGO1AGO1EIF2C1FUNCTION Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) or short interfering RNAs (siRNAs), and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for transcriptional gene silencing (TGS) of promoter regions which are complementary to bound short antigene RNAs (agRNAs).SUBUNIT Interacts with DDB1, DDX5, DDX6, DHX30, DHX36, DDX47, DICER1, AGO2, ELAVL1, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, MOV10, PABPC1, PRMT5, RBM4, SART3, TNRC6B, UPF1 and YBX1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with LIMD1, WTIP and AJUBA. Interacts with APOBEC3F, APOBEC3G and APOBEC3H.MISCELLANEOUS Lacks RNA cleavage activity due to the absence of the conserved His at position 805, but also because it binds the RNA in a subtly different manner that precludes efficient cleavage.SIMILARITY Belongs to the argonaute family. Ago subfamily.UniProtQ9UL181EQUAL857EQUALReactome Database ID Release 75210616Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210616ReactomeR-HSA-2106161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210616.1AGO3EIF2C3Argonaute-3Reactome DB_ID: 210615UniProt:Q9H9G7 AGO3AGO3EIF2C3FUNCTION Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Proposed to be involved in stabilization of small RNA derivates (siRNA) derived from processed RNA polymerase III-transcribed Alu repeats containing a DR2 retinoic acid response element (RARE) in stem cells and in the subsequent siRNA-dependent degradation of a subset of RNA polymerase II-transcribed coding mRNAs by recruiting a mRNA decapping complex involving EDC4. Possesses RNA slicer activity but only on select RNAs bearing 5'- and 3'-flanking sequences to the region of guide-target complementarity (PubMed:29040713).SUBUNIT Interacts with EIF4B, IMP8, PRMT5 and TNRC6B. Interacts with APOBEC3F, APOBEC3G and APOBEC3H. Interacts with EDC4.SIMILARITY Belongs to the argonaute family. Ago subfamily.UniProtQ9H9G71EQUAL860EQUALReactome Database ID Release 75210615Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210615ReactomeR-HSA-2106151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210615.1AGO4EIF2C4Argonaute-4Reactome DB_ID: 210612UniProt:Q9HCK5 AGO4AGO4EIF2C4KIAA1567FUNCTION Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for RNA-directed transcription and replication of the human hapatitis delta virus (HDV).SUBUNIT Interacts with EIF4B, IMP8, PRMT5, TNRC6A and TNRC6B (PubMed:19167051). Interacts with ZFP36 (PubMed:15766526).SIMILARITY Belongs to the argonaute family. Ago subfamily.UniProtQ9HCK51EQUAL861EQUALReactome Database ID Release 75210612Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210612ReactomeR-HSA-2106121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210612.1Reactome Database ID Release 75210613Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=210613ReactomeR-HSA-2106131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-210613.111Reactome Database ID Release 752318739Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318739ReactomeR-HSA-23187391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318739.11Reactome Database ID Release 752318738Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318738ReactomeR-HSA-23187381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318738.1Reactome Database ID Release 752318737Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318737ReactomeR-HSA-23187371Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318737.1PTEN mRNA:miR-26A RISCReactome DB_ID: 231875011Reactome Database ID Release 752318750Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318750ReactomeR-HSA-23187501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318750.1Reactome Database ID Release 752318752Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2318752ReactomeR-HSA-23187527Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2318752.719487573Pubmed2009The PTEN-regulating microRNA miR-26a is amplified in high-grade glioma and facilitates gliomagenesis in vivoHuse, Jason TBrennan, CameronHambardzumyan, DoloresWee, BoyoungPena, JohnRouhanifard, Sara HSohn-Lee, Cherinle Sage, CarlosAgami, ReuvenTuschl, ThomasHolland, Eric CGenes Dev. 23:1327-3720080666Pubmed2010Integrative genome analysis reveals an oncomir/oncogene cluster regulating glioblastoma survivorshipKim, HyunsooHuang, WeiJiang, XiuliPennicooke, BrentonPark, Peter JJohnson, Mark DProc. Natl. Acad. Sci. U.S.A. 107:2183-8LEFT-TO-RIGHTPTEN mRNA translation negatively regulated by microRNAsPTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing PTEN protein expression from the remaining allele (Huse et al. 2009). Other microRNAs, which may also be altered in cancer, such as miR-17, miR-19a, miR-19b, miR-20a, miR-20b, miR-21, miR-22, miR-25, miR-93, miR-106a, miR-106b, miR 205, and miR 214, also bind PTEN mRNA and inhibit its translation into protein (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Zhang et al. 2010, Tay et al. 2011, Qu et al. 2012, Cai et al. 2013).Authored: Orlic-Milacic, M, 2012-07-18Reviewed: Thorpe, Lauren, 2012-08-13Reviewed: Yuzugullu, Haluk, 2012-08-13Reviewed: Zhao, Jean J, 2012-08-13Edited: Matthews, L, 2012-08-03PTENPhosphatidylinositol-3,4,5-trisphosphate 3-phosphatase PTENPTEN_HUMANMMAC1TEP1Reactome DB_ID: 199420UniProt:P60484 PTENPTENMMAC1TEP1FUNCTION Tumor suppressor. Acts as a dual-specificity protein phosphatase, dephosphorylating tyrosine-, serine- and threonine-phosphorylated proteins. Also acts as a lipid phosphatase, removing the phosphate in the D3 position of the inositol ring from phosphatidylinositol 3,4,5-trisphosphate, phosphatidylinositol 3,4-diphosphate, phosphatidylinositol 3-phosphate and inositol 1,3,4,5-tetrakisphosphate with order of substrate preference in vitro PtdIns(3,4,5)P3 &gt; PtdIns(3,4)P2 &gt; PtdIns3P &gt; Ins(1,3,4,5)P4 (PubMed:26504226, PubMed:16824732). The lipid phosphatase activity is critical for its tumor suppressor function. Antagonizes the PI3K-AKT/PKB signaling pathway by dephosphorylating phosphoinositides and thereby modulating cell cycle progression and cell survival. The unphosphorylated form cooperates with AIP1 to suppress AKT1 activation. Dephosphorylates tyrosine-phosphorylated focal adhesion kinase and inhibits cell migration and integrin-mediated cell spreading and focal adhesion formation. Plays a role as a key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. May be a negative regulator of insulin signaling and glucose metabolism in adipose tissue. The nuclear monoubiquitinated form possesses greater apoptotic potential, whereas the cytoplasmic nonubiquitinated form induces less tumor suppressive ability. In motile cells, suppresses the formation of lateral pseudopods and thereby promotes cell polarization and directed movement.ACTIVITY REGULATION Enzymatic activity is enhanced in the presence of phosphatidylserine.SUBUNIT Monomer. The unphosphorylated form interacts with the second PDZ domain of AIP1 and with DLG1 and MAST2 in vitro (PubMed:10646847, PubMed:10760291, PubMed:11707428). Interacts with MAGI2, MAGI3, MAST1 and MAST3, but neither with MAST4 nor with DLG5; interaction with MAGI2 increases protein stability (PubMed:10748157, PubMed:15951562). Interacts with NEDD4 (PubMed:17218260). Interacts with NDFIP1 and NDFIP2; in the presence of NEDD4 or ITCH, this interaction promotes PTEN ubiquitination (PubMed:25801959, PubMed:20534535). Interacts (via C2 domain) with FRK (PubMed:19345329). Interacts with USP7; the interaction is direct (PubMed:18716620). Interacts with ROCK1 (By similarity). Interacts with XIAP/BIRC4 (PubMed:19473982). Interacts with STK11; the interaction phosphorylates PTEN (PubMed:15987703). Interacts with PPP1R16B (PubMed:25007873). Interacts with NOP53; regulates PTEN phosphorylation and increases its stability (PubMed:15355975).TISSUE SPECIFICITY Expressed at a relatively high level in all adult tissues, including heart, brain, placenta, lung, liver, muscle, kidney and pancreas.INDUCTION Down-regulated by TGFB1.DOMAIN The C2 domain binds phospholipid membranes in vitro in a Ca(2+)-independent manner; this binding is important for its tumor suppressor function.PTM Constitutively phosphorylated by CK2 under normal conditions. Phosphorylated in vitro by MAST1, MAST2, MAST3 and STK11. Phosphorylation results in an inhibited activity towards PIP3. Phosphorylation can both inhibit or promote PDZ-binding. Phosphorylation at Tyr-336 by FRK/PTK5 protects this protein from ubiquitin-mediated degradation probably by inhibiting its binding to NEDD4. Phosphorylation by ROCK1 is essential for its stability and activity. Phosphorylation by PLK3 promotes its stability and prevents its degradation by the proteasome.PTM Monoubiquitinated; monoubiquitination is increased in presence of retinoic acid. Deubiquitinated by USP7; leading to its nuclear exclusion. Monoubiquitination of one of either Lys-13 and Lys-289 amino acid is sufficient to modulate PTEN compartmentalization. Ubiquitinated by XIAP/BIRC4.DISEASE PTEN mutations are found in a subset of patients with Proteus syndrome, a genetically heterogeneous condition. The molecular diagnosis of PTEN mutation positive cases classifies Proteus syndrome patients as part of the PTEN hamartoma syndrome spectrum. As such, patients surviving the early years of Proteus syndrome are likely at a greater risk of developing malignancies.DISEASE A microdeletion of chromosome 10q23 involving BMPR1A and PTEN is a cause of chromosome 10q23 deletion syndrome, which shows overlapping features of the following three disorders: Bannayan-Zonana syndrome, Cowden disease and juvenile polyposis syndrome.SIMILARITY Belongs to the PTEN phosphatase protein family.UniProtP604842EQUAL403EQUALReactome Database ID Release 75199420Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199420ReactomeR-HSA-1994202Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199420.2Reactome Database ID Release 752321904Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2321904ReactomeR-HSA-23219044Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2321904.4INHIBITIONactiveUnit: #Complex10Reactome Database ID Release 752321906Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2321906ReactomeR-HSA-23219061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2321906.1LEFT-TO-RIGHTTP53 binds regulatory elements of SESN1,2,3 genesTP53 (p53) binds to the p53 response element in the intron 2 of SESN1 gene and stimulates transcription of SESN1 transcripts SESN1-1 and SESN1-3, also known as PA26 T2 and PA26 T3 (Velasco-Miguel et al. 1999). Recently, TP53 binding to SESN2 gene regulatory elements has been identified by ChIPseq (Menendez et al. 2013), and SESN2 gene expression was previously shown to be responsive to TP53 (Budanov et al. 2002). Rat ortholog of SESN3 was shown to possess p53 binding sites in the promoter region, but direct binding of TP53 to regulatory elements of human SESN3 has not been examined (Brynczka et al. 2007). Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23Converted from EntitySet in ReactomeSESN1,2,3 GenesReactome DB_ID: 5629150SESN2 GeneReactome DB_ID: 5629145ENSEMBL:ENSG00000130766 SESN2SESN2Hi95SEST2ENSEMBLENSG00000130766Reactome Database ID Release 755629145Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629145ReactomeR-HSA-56291451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629145.1SESN1 GeneReactome DB_ID: 5629151ENSEMBL:ENSG00000080546 SESN1SESN1PA26SEST1ENSEMBLENSG00000080546Reactome Database ID Release 755629151Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629151ReactomeR-HSA-56291511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629151.1SESN3 GeneReactome DB_ID: 5629147ENSEMBL:ENSG00000149212 SESN3SESN3SEST3ENSEMBLENSG00000149212Reactome Database ID Release 755629147Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629147ReactomeR-HSA-56291471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629147.1Reactome Database ID Release 755629150Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629150ReactomeR-HSA-56291502Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629150.2TP53 Tetramer:SESN1,2,3 GenesReactome DB_ID: 562918011Reactome Database ID Release 755629180Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629180ReactomeR-HSA-56291801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629180.1Reactome Database ID Release 755629187Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629187ReactomeR-HSA-56291873Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629187.39926927Pubmed1999PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genesVelasco-Miguel, SBuckbinder, LJean, PGelbert, LTalbott, RLaidlaw, JSeizinger, BKley, NOncogene 18:127-3712203114Pubmed2002Identification of a novel stress-responsive gene Hi95 involved in regulation of cell viabilityBudanov, Andrei VShoshani, TziporaFaerman, AlexanderZelin, ElenaKamer, IrisKalinski, HagarGorodin, SvetlanaFishman, AllaChajut, AyeletEinat, PazSkaliter, RamiGudkov, Andrei VChumakov, Peter MFeinstein, ElenaOncogene 21:6017-3117540029Pubmed2007NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiationBrynczka, ChristopherLabhart, PaulMerrick, B AlexBMC Genomics 8:13923775793Pubmed2013Diverse stresses dramatically alter genome-wide p53 binding and transactivation landscape in human cancer cellsMenendez, DanielNguyen, Thuy-AiFreudenberg, Johannes MMathew, Viju JAnderson, Carl WJothi, RajaResnick, Michael ANucleic Acids Res. 41:7286-301LEFT-TO-RIGHTTP53 stimulates expression of SESN1,2,3 genesSestrins (SESN) are a small family of stress-sensitive gene that are conserved across several species. Mammals express three different SESN family members characterized as SESN1-3. Sestrin genes, SESN1, SESN2 and SESN3, are upregulated in response to TP53-mediated transcriptional regulation. SESN1 and SESN2 were classified as members of the growth arrest and DNA damage (GADD) gene family that can regulate cell growth and viability under different cellular pressures. In particular, p53 negatively modulates the mTOR pahtway via SESN1 and SESN2 upregulation (Feng 2010). SESN3 was identified shortly after SESN2 through in silico analysis and was found to be a target of the forkhead transcription factor (FOXO) family. A specific TP53 binding site on the human SESN3 promoter has not been identified yet, but was found in the rat ortholog (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23Converted from EntitySet in ReactomeSESN1,2,3Reactome DB_ID: 5629191Hi95SESN2Sestrin-2Reactome DB_ID: 5629143UniProt:P58004 SESN2SESN2Hi95SEST2FUNCTION Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling (PubMed:18692468, PubMed:25263562, PubMed:25457612, PubMed:26449471, PubMed:26612684, PubMed:26586190). Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:26449471, PubMed:26586190). This stress-inducible metabolic regulator also plays a role in protection against oxidative and genotoxic stresses. May negatively regulate protein translation in response to endoplasmic reticulum stress, via TORC1 (PubMed:24947615). May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085). May also mediate TP53 inhibition of TORC1 signaling upon genotoxic stress (PubMed:18692468). Has an alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (PubMed:26612684). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (PubMed:19113821).SUBUNIT Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (PubMed:25263562, PubMed:25457612, PubMed:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). May interact with the TORC2 complex (By similarity). Interacts with KEAP1, RBX1, SQSTM and ULK1; to regulate the degradation of KEAP1 (PubMed:23274085, PubMed:25040165). May also associate with the complex composed of TSC1, TSC2 and the AMP-responsive protein kinase/AMPK to regulate TORC1 signaling (PubMed:18692468). May interact with PRDX1 (PubMed:15105503).TISSUE SPECIFICITY Widely expressed.INDUCTION Up-regulated by hypoxia and DNA damage (PubMed:12203114). Up-regulated by treatments inducing endoplasmic reticulum stress (PubMed:24947615).DOMAIN Composed of an N-terminal domain that has an alkylhydroperoxide reductase activity and a C-terminal domain that mediates interaction with GATOR2 through which it regulates TORC1 signaling.PTM Phosphorylated by ULK1 at multiple sites.SIMILARITY Belongs to the sestrin family.UniProtP580041EQUAL480EQUALReactome Database ID Release 755629143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629143ReactomeR-HSA-56291431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629143.1Converted from EntitySet in ReactomeSESN1-1,SESN1-3Sestrin 1 isoforms T2 and T3PA26 isoforms T2 and T3Reactome DB_ID: 5629186SESN1-1Sestrin-1 isoform T2p53-regulated protein PA26 isoform T2PA26 isoform T2Reactome DB_ID: 5629148UniProt:Q9Y6P5-1 SESN1SESN1PA26SEST1FUNCTION Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:25263562, PubMed:26449471). This stress-inducible metabolic regulator may also play a role in protection against oxidative and genotoxic stresses (By similarity). May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085). May have an alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (By similarity). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (By similarity).SUBUNIT Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (PubMed:25263562, PubMed:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). Interacts with KEAP1, RBX1 and SQSTM1; in the SQSTM1-dependent autophagic degradation of KEAP1 (PubMed:23274085). May interact with PRDX1 (PubMed:15105503).TISSUE SPECIFICITY Widely expressed.INDUCTION Isoform T2 and isoform T3 are induced by genotoxic stress (UV, gamma-irradiation and cytotoxic drugs) in a p53/TP53-dependent manner. Isoform T1 is not induced by p53/TP53.DOMAIN Composed of an N-terminal domain that has an alkylhydroperoxide reductase activity and a C-terminal domain that mediates interaction with GATOR2 through which it regulates TORC1 signaling.SIMILARITY Belongs to the sestrin family.UniProt IsoformQ9Y6P5-11EQUAL492EQUALReactome Database ID Release 755629148Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629148ReactomeR-HSA-56291481Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629148.1SESN1-3Sestrin-1 isoform T3PA26 isoform T3Reactome DB_ID: 5629179UniProt:Q9Y6P5-3 SESN1SESN1PA26SEST1FUNCTION Functions as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway through the GATOR complex. In absence of leucine, binds the GATOR subcomplex GATOR2 and prevents TORC1 signaling. Binding of leucine to SESN2 disrupts its interaction with GATOR2 thereby activating the TORC1 signaling pathway (PubMed:25263562, PubMed:26449471). This stress-inducible metabolic regulator may also play a role in protection against oxidative and genotoxic stresses (By similarity). May positively regulate the transcription by NFE2L2 of genes involved in the response to oxidative stress by facilitating the SQSTM1-mediated autophagic degradation of KEAP1 (PubMed:23274085). May have an alkylhydroperoxide reductase activity born by the N-terminal domain of the protein (By similarity). Was originally reported to contribute to oxidative stress resistance by reducing PRDX1 (PubMed:15105503). However, this could not be confirmed (By similarity).SUBUNIT Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is negatively regulated by leucine (PubMed:25263562, PubMed:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). Interacts with KEAP1, RBX1 and SQSTM1; in the SQSTM1-dependent autophagic degradation of KEAP1 (PubMed:23274085). May interact with PRDX1 (PubMed:15105503).TISSUE SPECIFICITY Widely expressed.INDUCTION Isoform T2 and isoform T3 are induced by genotoxic stress (UV, gamma-irradiation and cytotoxic drugs) in a p53/TP53-dependent manner. Isoform T1 is not induced by p53/TP53.DOMAIN Composed of an N-terminal domain that has an alkylhydroperoxide reductase activity and a C-terminal domain that mediates interaction with GATOR2 through which it regulates TORC1 signaling.SIMILARITY Belongs to the sestrin family.UniProt IsoformQ9Y6P5-31EQUAL426EQUALReactome Database ID Release 755629179Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629179ReactomeR-HSA-56291791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629179.1Reactome Database ID Release 755629186Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629186ReactomeR-HSA-56291861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629186.1SESN3Sestrin-3Reactome DB_ID: 5629144UniProt:P58005 SESN3SESN3SEST3FUNCTION May function as an intracellular leucine sensor that negatively regulates the TORC1 signaling pathway (PubMed:25263562). May also regulate the insulin-receptor signaling pathway through activation of TORC2 (By similarity). This metabolic regulator may also play a role in protection against oxidative and genotoxic stresses (By similarity).SUBUNIT Interacts with the GATOR2 complex which is composed of MIOS, SEC13, SEH1L, WDR24 and WDR59; the interaction is not regulated by leucine (PubMed:25263562, PubMed:26449471). Interacts with RRAGA, RRAGB, RRAGC and RRAGD; may function as a guanine nucleotide dissociation inhibitor for RRAGs and regulate them (PubMed:25259925). Interacts with the TORC2 complex; through RICTOR (By similarity).TISSUE SPECIFICITY Widely expressed.DOMAIN The C-terminal domain may mediate interaction with GATOR2 and regulation of TORC1 signaling.SIMILARITY Belongs to the sestrin family.UniProtP580051EQUAL492EQUALReactome Database ID Release 755629144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629144ReactomeR-HSA-56291441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629144.1Reactome Database ID Release 755629191Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629191ReactomeR-HSA-56291912Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629191.2Reactome Database ID Release 755629189Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629189ReactomeR-HSA-56291894Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629189.420182617Pubmed2010p53 regulation of the IGF-1/AKT/mTOR pathways and the endosomal compartmentFeng, ZhaohuiCold Spring Harb Perspect Biol 2:a001057ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 755629192Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629192ReactomeR-HSA-56291922Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629192.2LEFT-TO-RIGHT1.11.1PRDX1,2,5 catalyze TXN reduced + H2O2 => TXN oxidized + 2H2OPeroxiredoxin 1 (PRDX1), PRDX2, and PRDX5 in the cytosol reduce hydrogen peroxide (H2O2) with thioredoxin yielding oxidized thioredoxin and water (Yamashita et al. 1999, Lee et al. 2007, Nagy et al. 2011).Authored: May, B, 2013-05-05Reviewed: Kavdia, Mahendra, 2013-11-01Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: May, B, 2013-05-05TXNThioredoxinATL-derived factorADFSurface associated sulphydryl proteinSASPReactome DB_ID: 66000UniProt:P10599 TXNTXNTRDXTRXTRX1FUNCTION Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions (PubMed:2176490, PubMed:17182577, PubMed:19032234). Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity (PubMed:16408020, PubMed:17606900). Induces the FOS/JUN AP-1 DNA-binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity (PubMed:9108029, PubMed:11118054).FUNCTION ADF augments the expression of the interleukin-2 receptor TAC (IL2R/P55).SUBUNIT Homodimer; disulfide-linked (PubMed:9369469, PubMed:17260951). Interacts with TXNIP through the redox-active site (PubMed:17260951). Interacts with MAP3K5 and CASP3 (PubMed:15246877). In case of infection, interacts with S.typhimurium protein slrP (PubMed:19690162). Interacts with APEX1; the interaction stimulates the FOS/JUN AP-1 DNA-binding activity in a redox-dependent manner (PubMed:9108029).INDUCTION Up-regulated by ionizing radiation.PTM In the fully reduced protein, both Cys-69 and Cys-73 are nitrosylated in response to nitric oxide (NO). When two disulfide bonds are present in the protein, only Cys-73 is nitrosylated. Cys-73 can serve as donor for nitrosylation of target proteins.PTM In case of infection, ubiquitinated by S.typhimurium protein slrP, leading to its degradation.ALLERGEN Causes an allergic reaction in human (PubMed:17182577, PubMed:19032234, PubMed:21489611). Recombinant protein binds to IgE in atopic eczema-suffering patients allergic to opportunistic skin-colonizing yeast M.sympodialis. Intermediate cross-reactivity is detected between the recombinant thioredoxin from M.sympodialis (Mala s 13) and recombinant form of this protein. Skin-prick test (SPT) and atopy patch test (APT) with 5 patients confirm cross-reactivity between the two proteins (PubMed:17182577). Recombinant protein binds to IgE of patients suffering from allergic bronchopulmonary aspergillosis (ABPA) and cross-reacts extensively with recombinant thioredoxin proteins from A.fumigatus (Asp f 28 and Asp f 29) and Mala s 13. Causes a positive skin reaction and induces proliferation of the human peripheral blood mononuclear cells in ABPA patients allergic to this protein. Acts as an IgE-binding self-antigen in ABPA patients allergic to fungal thioredoxin (PubMed:19032234). In atopic dermatitis (AD)-suffering patients allergic to M.sympodialis, a cross-reactivity between Mala s 13 and this protein can be detected in T-cells of the peripheral blood and skin. Keratinocytes stimulated by interferon (IFN)-alpha and tumor necrosis factor (TNF)-alpha release thioredoxin, which then becomes available for cross-reactivity with Mala s 13-specific T cells. The autoreactive T cells identified include T-helper 1 (Th1), T-helper 2 (Th2), T-helper 17 (Th17) and T-helper 22 (Th22) phenotypes. Skinhoming T cells autoreactive to this protein may be relevant for cutaneous inflammation in patients with AD (PubMed:21489611).SIMILARITY Belongs to the thioredoxin family.UniProtP105992EQUAL105EQUALReactome Database ID Release 7566000Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=66000ReactomeR-HSA-660001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-66000.12ADF2xHC-TXNThioredoxin, oxidizedThioredoxinATL-derived factorSurface associated sulphydryl proteinSASPReactome DB_ID: 7366832EQUALL-cystine (cross-link)MODMOD:000342EQUAL105EQUALReactome Database ID Release 7573668Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73668ReactomeR-HSA-736682Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73668.2ACTIVATIONConverted from EntitySet in ReactomePRDX1,2,5Reactome DB_ID: 3341359PRDX1 dimerReactome DB_ID: 3341319PRDX1Peroxiredoxin-1 ecNumber1.11.1.15/ecNumberPRDX1_HUMANReactome DB_ID: 3341270UniProt:Q06830 PRDX1PRDX1PAGAPAGBTDPX2FUNCTION Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events. Might participate in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentrations of H(2)O(2) (PubMed:9497357). Reduces an intramolecular disulfide bond in GDPD5 that gates the ability to GDPD5 to drive postmitotic motor neuron differentiation (By similarity).SUBUNIT Homodimer; disulfide-linked, upon oxidation. 5 homodimers assemble to form a ring-like decamer (PubMed:18172504). Interacts with GDPD5; forms a mixed-disulfide with GDPD5 (By similarity). Interacts with SESN1 and SESN2 (PubMed:15105503). Interacts with FAM107A (PubMed:21969592).INDUCTION Constitutively expressed in most human cells; is induced to higher levels upon serum stimulation in untransformed and transformed cells.PTM Phosphorylated on Thr-90 during the M-phase, which leads to a more than 80% decrease in enzymatic activity.PTM The enzyme can be inactivated by further oxidation of the cysteine sulfenic acid (C(P)-SOH) to sulphinic acid (C(P)-SO2H) instead of its condensation to a disulfide bond. It can be reactivated by forming a transient disulfide bond with sulfiredoxin SRXN1, which reduces the cysteine sulfinic acid in an ATP- and Mg-dependent manner.MISCELLANEOUS The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this typical 2-Cys peroxiredoxin, C(R) is provided by the other dimeric subunit to form an intersubunit disulfide. The disulfide is subsequently reduced by thioredoxin.SIMILARITY Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.UniProtQ068302EQUAL199EQUALReactome Database ID Release 753341270Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341270ReactomeR-HSA-33412701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341270.12Reactome Database ID Release 753341319Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341319ReactomeR-HSA-33413191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341319.1PRDX2 dimerReactome DB_ID: 3341391PRDX2Peroxiredoxin-2 ecNumber1.11.1.15/ecNumberPRDX2_HUMANReactome DB_ID: 3341292UniProt:P32119 PRDX2PRDX2NKEFBTDPX1FUNCTION Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events. Might participate in the signaling cascades of growth factors and tumor necrosis factor-alpha by regulating the intracellular concentrations of H(2)O(2).SUBUNIT Homodimer; disulfide-linked, upon oxidation (PubMed:27892488). 5 homodimers assemble to form a ring-like decamer (PubMed:27892488). Interacts with TIPIN (PubMed:17141802).PTM The enzyme can be inactivated by further oxidation of the cysteine sulfenic acid (C(P)-SOH) to sulphinic acid (C(P)-SO2H) instead of its condensation to a disulfide bond. It can be reactivated by forming a transient disulfide bond with sulfiredoxin SRXN1, which reduces the cysteine sulfinic acid in an ATP- and Mg-dependent manner.MISCELLANEOUS The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this typical 2-Cys peroxiredoxin, C(R) is provided by the other dimeric subunit to form an intersubunit disulfide. The disulfide is subsequently reduced by thioredoxin.SIMILARITY Belongs to the peroxiredoxin family. AhpC/Prx1 subfamily.UniProtP321192EQUAL198EQUALReactome Database ID Release 753341292Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341292ReactomeR-HSA-33412921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341292.12Reactome Database ID Release 753341391Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341391ReactomeR-HSA-33413911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341391.1PRDX5Peroxiredoxin-5, mitochondrial ecNumber1.11.1.15/ecNumberPRDX5_HUMANReactome DB_ID: 3341350UniProt:P30044-2 PRDX5PRDX5ACR1SBBI10FUNCTION Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively. Plays a role in cell protection against oxidative stress by detoxifying peroxides and as sensor of hydrogen peroxide-mediated signaling events.SUBUNIT Monomer.TISSUE SPECIFICITY Widely expressed.MISCELLANEOUS The active site is a conserved redox-active cysteine residue, the peroxidatic cysteine (C(P)), which makes the nucleophilic attack on the peroxide substrate. The peroxide oxidizes the C(P)-SH to cysteine sulfenic acid (C(P)-SOH), which then reacts with another cysteine residue, the resolving cysteine (C(R)), to form a disulfide bridge. The disulfide is subsequently reduced by an appropriate electron donor to complete the catalytic cycle. In this atypical 2-Cys Prx, C(R) is present in the same subunit to form an intramolecular disulfide. The disulfide is subsequently reduced by thioredoxin.SIMILARITY Belongs to the peroxiredoxin family. Prx5 subfamily.UniProt IsoformP30044-253EQUAL214EQUALReactome Database ID Release 753341350Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341350ReactomeR-HSA-33413501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341350.1Reactome Database ID Release 753341359Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341359ReactomeR-HSA-33413591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341359.1GENE ONTOLOGYGO:0008379Reactome Database ID Release 753341280Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341280Reactome Database ID Release 753341343Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341343ReactomeR-HSA-33413433Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3341343.310514471Pubmed1999Characterization of human and murine PMP20 peroxisomal proteins that exhibit antioxidant activity in vitroYamashita, HAvraham, SJiang, SLondon, RVan Veldhoven, Paul PSubramani, SRogers, R AAvraham, HJ. Biol. Chem. 274:29897-90417519234Pubmed2007Human peroxiredoxin 1 and 2 are not duplicate proteins: the unique presence of CYS83 in Prx1 underscores the structural and functional differences between Prx1 and Prx2Lee, WeonsupChoi, Kyoung-SooRiddell, JonahIp, ClementGhosh, DebashisPark, Jong-HoonPark, Young-MeeJ. Biol. Chem. 282:22011-2221385867Pubmed2011Model for the exceptional reactivity of peroxiredoxins 2 and 3 with hydrogen peroxide: a kinetic and computational studyNagy, PéterKarton, AmirBetz, AndreaPeskin, Alexander VPace, PaulO'Reilly, Robert JHampton, Mark BRadom, LeoWinterbourn, Christine CJ. Biol. Chem. 286:18048-55LEFT-TO-RIGHT1.8.1.9regeneration of active (reduced) Thioredoxinthioredoxin, oxidized + NADPH + H+ => thioredoxin, reduced + NADP+Cytosolic thioredoxin reductase catalyzes the reaction of thioredoxin, oxidized and NADPH + H+ to form thioredoxin, reduced and NADP+ (Urig et al. 2006).Authored: Jassal, B, 2003-06-17 09:00:25Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Jassal, B, 2003-06-17 09:00:25Edited: D'Eustachio, P, 2010-02-05ACTIVATION2xTXNRD1:2xFADTNXRD1:FAD dimerthioredoxin reductase holoenzymeThioredoxin reductase-FAD complexReactome DB_ID: 735322TRTXNRD1thioredoxin reductase 1Thioredoxin reductase, cytoplasmic precursor (EC 1.8.1.9) (TR)Thioredoxin reductase, cytoplasmic precursor TR1Reactome DB_ID: 73531UniProt:Q16881 TXNRD1TXNRD1GRIM12KDRFFUNCTION Isoform 1 may possess glutaredoxin activity as well as thioredoxin reductase activity and induces actin and tubulin polymerization, leading to formation of cell membrane protrusions. Isoform 4 enhances the transcriptional activity of estrogen receptors alpha and beta while isoform 5 enhances the transcriptional activity of the beta receptor only. Isoform 5 also mediates cell death induced by a combination of interferon-beta and retinoic acid.SUBUNIT Homodimer. Isoform 4 interacts with ESR1 and ESR2. Interacts with HERC5.TISSUE SPECIFICITY Isoform 1 is expressed predominantly in Leydig cells (at protein level). Also expressed in ovary, spleen, heart, liver, kidney and pancreas and in a number of cancer cell lines. Isoform 4 is widely expressed with highest levels in kidney, testis, uterus, ovary, prostate, placenta and fetal liver.INDUCTION Isoform 5 is induced by a combination of interferon-beta and retinoic acid (at protein level). Isoform 1 is induced by estradiol or testosterone in HeLa cells.DOMAIN The N-terminal glutaredoxin domain found in isoform 1 does not contain the C-P-Y-C redox-active motif normally found in glutaredoxins and has been found to be inactive in classical glutaredoxin assays.PTM The N-terminus of isoform 5 is blocked.PTM ISGylated.MISCELLANEOUS The thioredoxin reductase active site is a redox-active disulfide bond. The selenocysteine residue is also essential for catalytic activity.SIMILARITY Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family.UniProtQ168811EQUAL649EQUALReactome Database ID Release 7573531Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73531ReactomeR-HSA-735311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73531.12Reactome Database ID Release 7573532Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73532ReactomeR-HSA-735322Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73532.2GENE ONTOLOGYGO:0004791Reactome Database ID Release 7573533Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73533Reactome Database ID Release 7573646Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=73646ReactomeR-HSA-736464Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-73646.416750198Pubmed2006Truncated mutants of human thioredoxin reductase 1 do not exhibit glutathione reductase activityUrig, SLieske, JFritz-Wolf, KIrmler, ABecker, KFEBS Lett 580:3595-600LEFT-TO-RIGHT1.11.1.7PRDX1 overoxidizesThe activity of eukaryotic PRDX1 gradually decreases with time, which is due to the overoxidation of the catalytic cysteine C52. Normally, oxidized cysteine C52-SOH is generated as a catalytic intermediate, which is subsequently reduced by thioredoxin. Occasionally, further oxidation happens, generating C52-SOOH , where the catalytic cysteine is converted to cysteine-sulfinic acid. This over-oxidation cannot be reversed by thioredoxin (Yang et al. 2002, Budanov et al. 2004). Bacterial peroxiredoxin AhpC does not undergo over-oxidation due to structural difference (Wood et al. 2003).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-232HOOS-C52-PRDX1 dimerReactome DB_ID: 56318821HOOS-C52-PRDX1PRDX1 with Cys52-sulfinic acidReactome DB_ID: 562919852EQUALL-cysteine sulfinic acidMODMOD:002672EQUAL199EQUALReactome Database ID Release 755629198Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5629198ReactomeR-HSA-56291981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5629198.11Reactome Database ID Release 755631882Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5631882ReactomeR-HSA-56318821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5631882.1ACTIVATIONactiveUnit: #Protein25GENE ONTOLOGYGO:0004601Reactome Database ID Release 755631899Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5631899Reactome Database ID Release 755631885Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5631885ReactomeR-HSA-56318852Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5631885.212161445Pubmed2002Inactivation of human peroxiredoxin I during catalysis as the result of the oxidation of the catalytic site cysteine to cysteine-sulfinic acidYang, Kap-SeokKang, Sang WonWoo, Hyun AeHwang, Sung ChulChae, Ho ZoonKim, KanghwaRhee, Sue GooJ. Biol. Chem. 277:38029-3612714747Pubmed2003Peroxiredoxin evolution and the regulation of hydrogen peroxide signalingWood, Zachary APoole, Leslie BKarplus, P AndrewScience 300:650-315105503Pubmed2004Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpDBudanov, Andrei VSablina, Anna AFeinstein, ElenaKoonin, Eugene VChumakov, Peter MScience 304:596-600LEFT-TO-RIGHTSestrins bind overoxidized PRDX1SESN1,2,3 bind overoxidized PRDX1Sestrins (SESN1, SESN2 and likely SESN3) bind overoxidized PRDX1, in which the catalytic cysteine C52 has been converted to cysteine-sulfinic acid. Among all peroxiredoxins, PRDX1 is the most abundant member of the PRDX family. The major function is to protect cells against reactive oxygen species (ROS), thus impacting on cell proliferation and survival (Gong et al. 2015). While several reports state that sestrins reduce overoxidized PRDX1 to the catalytically active homodimer (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009), there are conflicting reports claiming that sestrins do not possess cysteine sulfinyl reductase activity (Woo et al. 2009). Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23SESN1,2,3:HOOS-C52-PRDX1 dimerReactome DB_ID: 563190211Reactome Database ID Release 755631902Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5631902ReactomeR-HSA-56319021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5631902.1Reactome Database ID Release 755631903Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5631903ReactomeR-HSA-56319033Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5631903.325579166Pubmed2015Peroxiredoxin 1 promotes tumorigenesis through regulating the activity of mTOR/p70S6K pathway in esophageal squamous cell carcinomaGong, FanghuaHou, GuiqinLiu, HongtaoZhang, MingzhiMed. Oncol. 32:45518344994Pubmed2008Synaptic NMDA receptor activity boosts intrinsic antioxidant defensesPapadia, SofiaSoriano, Francesc XLéveillé, FrédéricMartel, Marc-AndreDakin, Kelly AHansen, Henrik HKaindl, AngelaSifringer, MarcoFowler, JillStefovska, VanyaMcKenzie, GrahameCraigon, MarieCorriveau, RoderickGhazal, PeterHorsburgh, KarenYankner, Bruce AWyllie, David J AIkonomidou, ChrysanthyHardingham, Giles ENat. Neurosci. 11:476-8719822145Pubmed2009Role of sestrin2 in peroxide signaling in macrophagesEssler, SilkeDehne, NathalieBrüne, BernhardFEBS Lett. 583:3531-519113821Pubmed2009Sestrin 2 is not a reductase for cysteine sulfinic acid of peroxiredoxinsWoo, Hyun AeBae, Soo HanPark, SunjooRhee, Sue GooAntioxid. Redox Signal. 11:739-45LEFT-TO-RIGHT2.7.11.11p-AMPK phosphorylates TSC1:TSC2Activated AMPK (phosphorylated on the alpha subunit and with AMP bound) phosphorylates TSC2 (also known as tuberin) on Ser-1387, thereby activating the GTPase activating protein (GAP) activity of the Tuberous Sclerosis Complex (TSC). The TSC tumor suppressor is a critical upstream inhibitor of the mTORC1 complex. TSC is a GTPase-activating protein that stimulates the intrinsic GTPase activity of the small G-protein Rheb. This inactivates Rheb by stimulating its GTPase activity. The GDP-bound form of Rheb looses the ability to activate the kinase activity of the mTORC1 complex (Sancak et al. 2007). Loss of TSC1 or TSC2 leads to hyperactivation of mTORC1. <br><br>Phosphorylation of TSC1 and TSC2 serves as an integration point for a wide variety of environmental signals that regulate mTORC1 (Sabatini 2006). Mitogen-activated kinases including Akt, Erk, and Rsk directly phosphorylate TSC2, leading to its inactivation by an unknown mechanism. Another Akt substrate, PRAS40, was recently shown to bind and inhibit the mTORC1 complex. Upon phosphorylation by Akt, PRAS40 no longer inhibits mTORC1 (Sancak et al. 2007; Vander Haar et al. 2007).Authored: Katajisto, P, Makela, T, Wu, J, 2008-11-19Reviewed: Zwartkruis, Fried J T, 2015-05-14Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Jassal, B, 2008-11-19 15:14:38TSC1:TSC2Reactome DB_ID: 165175TSC2TuberinTSC2_HUMANReactome DB_ID: 2980548UniProt:P49815 TSC2TSC2TSC4FUNCTION In complex with TSC1, this tumor suppressor inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:15340059). May also play a role in microtubule-mediated protein transport (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity).SUBUNIT Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex thereby stabilizing TSC2 (PubMed:29127155). Interacts with TSC1 and HERC1; the interaction with TSC1 stabilizes TSC2 and prevents the interaction with HERC1 (PubMed:9580671, PubMed:10585443, PubMed:15963462, PubMed:16464865). May also interact with the adapter molecule RABEP1 (PubMed:9045618). The final complex may contain TSC2 and RABEP1 linked to RAB5 (PubMed:9045618). Interacts with HSPA1 and HSPA8 (PubMed:15963462). Interacts with DAPK1 (PubMed:18974095). Interacts with FBXW5 (PubMed:18381890). Interacts with NAA10 (via C-terminal domain) (PubMed:20145209). Interacts with RRAGA (polyubiquitinated) (PubMed:25936802). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL38; this interaction inhibits cellular stress response mediated by mTORC1.TISSUE SPECIFICITY Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.PTM Phosphorylation at Ser-1387, Ser-1418 or Ser-1420 does not affect interaction with TSC1. Phosphorylation at Ser-939 and Thr-1462 by PKB/AKT1 is induced by growth factor stimulation. Phosphorylation by AMPK activates it and leads to negatively regulates the mTORC1 complex. Phosphorylated at Ser-1798 by RPS6KA1; phosphorylation inhibits TSC2 ability to suppress mTORC1 signaling. Phosphorylated by DAPK1.PTM Ubiquitinated by the DCX(FBXW5) E3 ubiquitin-protein ligase complex, leading to its subsequent degradation. Ubiquitinated by MYCBP2 independently of its phosphorylation status leading to subsequent degradation; association with TSC1 protects from ubiquitination.UniProtP498151EQUAL1807EQUALReactome Database ID Release 752980548Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2980548ReactomeR-HSA-29805481Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2980548.11TSC1Reactome DB_ID: 5672338UniProt:Q92574 TSC1TSC1KIAA0243TSCFUNCTION In complex with TSC2, inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Seems not to be required for TSC2 GAP activity towards RHEB (PubMed:15340059). Implicated as a tumor suppressor. Involved in microtubule-mediated protein transport, but this seems to be due to unregulated mTOR signaling (By similarity). Acts as a co-chaperone for HSP90AA1 facilitating HSP90AA1 chaperoning of protein clients such as kinases, TSC2 and glucocorticoid receptor NR3C1 (PubMed:29127155). Increases ATP binding to HSP90AA1 and inhibits HSP90AA1 ATPase activity (PubMed:29127155). Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins (PubMed:29127155). Recruits TSC2 to HSP90AA1 and stabilizes TSC2 by preventing the interaction between TSC2 and ubiquitin ligase HERC1 (PubMed:16464865, PubMed:29127155).SUBUNIT Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones STIP1/HOP, CDC37, PPP5C, PTGES3/p23, TSC1 and client protein TSC2 (PubMed:29127155). Forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Forms a complex containing HSP90AA1, TSC1 and TSC2; TSC1 is required to recruit TCS2 to the complex (PubMed:29127155). Interacts (via C-terminus) with the closed form of HSP90AA1 (via the middle domain and TPR repeat-binding motif) (PubMed:29127155). Interacts with TSC2; the interaction stabilizes TSC2 and prevents TSC2 self-aggregation (PubMed:10585443, PubMed:15963462, PubMed:16464865, PubMed:9580671, PubMed:9809973, PubMed:29127155, PubMed:28215400). Interacts with DOCK7 (PubMed:15963462). Interacts with FBXW5 (PubMed:18381890). Interacts with TBC1D7 (PubMed:17658474). Interacts with WDR45B (PubMed:28561066). Interacts with RPAP3 and URI1 (PubMed:28561026).TISSUE SPECIFICITY Highly expressed in skeletal muscle, followed by heart, brain, placenta, pancreas, lung, liver and kidney. Also expressed in embryonic kidney cells.DOMAIN The C-terminal putative coiled-coil domain is necessary for interaction with TSC2.PTM Phosphorylation at Ser-505 does not affect interaction with TSC2.UniProtQ925741EQUAL1164EQUALReactome Database ID Release 755672338Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5672338ReactomeR-HSA-56723381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5672338.11Reactome Database ID Release 75165175Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165175ReactomeR-HSA-1651751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165175.1ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 113592ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 75113592Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113592ReactomeR-ALL-1135924Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113592.4COMPOUNDC00002ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 29370ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 7529370Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29370ReactomeR-ALL-293704Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29370.4COMPOUNDC00008TSC1:p-S1387-TSC2Reactome DB_ID: 381855plasma membraneGENE ONTOLOGYGO:0005886TSC2p-S1387-TSC2TuberinTSC2_HUMANReactome DB_ID: 31327691387EQUALO-phospho-L-serineMODMOD:000461EQUAL1807EQUALReactome Database ID Release 753132769Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3132769ReactomeR-HSA-31327691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3132769.11TSC1Reactome DB_ID: 1651691EQUAL1164EQUALReactome Database ID Release 75165169Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165169ReactomeR-HSA-1651691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165169.11Reactome Database ID Release 75381855Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381855ReactomeR-HSA-3818551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381855.1ACTIVATIONp-AMPK heterotrimer:AMPReactome DB_ID: 380931AMPadenosine 5'-monophosphateAdenylic acidAdenylate5'-AMP5'-Adenylic acid5'-Adenosine monophosphateAdenosine 5'-phosphateReactome DB_ID: 76577adenosine 5'-monophosphate [ChEBI:16027]adenosine 5'-monophosphateChEBICHEBI:16027Reactome Database ID Release 7576577Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=76577ReactomeR-ALL-765774Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-76577.4COMPOUNDC000201p-AMPK heterotrimerReactome DB_ID: 380934Converted from EntitySet in Reactomep-AMPK alphaReactome DB_ID: 381844p-T172-PRKAA2p-T172-AMPK alpha2Reactome DB_ID: 200417UniProt:P54646 PRKAA2PRKAA2AMPKAMPK2FUNCTION Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. Involved in insulin receptor/INSR internalization (PubMed:25687571). AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. In that process also activates WDR45 (PubMed:28561066). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1. Plays an important role in the differential regulation of pro-autophagy (composed of PIK3C3, BECN1, PIK3R4 and UVRAG or ATG14) and non-autophagy (composed of PIK3C3, BECN1 and PIK3R4) complexes, in response to glucose starvation. Can inhibit the non-autophagy complex by phosphorylating PIK3C3 and can activate the pro-autophagy complex by phosphorylating BECN1 (By similarity).ACTIVITY REGULATION Activated by phosphorylation on Thr-172. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-172. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-172. ADP also stimulates Thr-172 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-172, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol. Salicylate/aspirin directly activates kinase activity, primarily by inhibiting Thr-172 dephosphorylation.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2. Associates with internalized insulin receptor/INSR complexes on Golgi/endosomal membranes; PRKAA2/AMPK2 together with ATIC and HACD3/PTPLAD1 is proposed to be part of a signaling network regulating INSR autophosphorylation and endocytosis (PubMed:25687571).DOMAIN The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.PTM Ubiquitinated.PTM Phosphorylated at Thr-172 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-172 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-172, but at much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK. Dephosphorylated by PPM1A and PPM1B at Thr-172 (mediated by STK11/LKB1).SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.UniProtP54646172EQUALO-phospho-L-threonineMODMOD:000471EQUAL552EQUALReactome Database ID Release 75200417Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200417ReactomeR-HSA-2004171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200417.1p-T183-PRKAA1p-T183-AMPK alpha1Reactome DB_ID: 380964UniProt:Q13131 PRKAA1PRKAA1AMPK1FUNCTION Catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Regulates lipid synthesis by phosphorylating and inactivating lipid metabolic enzymes such as ACACA, ACACB, GYS1, HMGCR and LIPE; regulates fatty acid and cholesterol synthesis by phosphorylating acetyl-CoA carboxylase (ACACA and ACACB) and hormone-sensitive lipase (LIPE) enzymes, respectively. Regulates insulin-signaling and glycolysis by phosphorylating IRS1, PFKFB2 and PFKFB3. AMPK stimulates glucose uptake in muscle by increasing the translocation of the glucose transporter SLC2A4/GLUT4 to the plasma membrane, possibly by mediating phosphorylation of TBC1D4/AS160. Regulates transcription and chromatin structure by phosphorylating transcription regulators involved in energy metabolism such as CRTC2/TORC2, FOXO3, histone H2B, HDAC5, MEF2C, MLXIPL/ChREBP, EP300, HNF4A, p53/TP53, SREBF1, SREBF2 and PPARGC1A. Acts as a key regulator of glucose homeostasis in liver by phosphorylating CRTC2/TORC2, leading to CRTC2/TORC2 sequestration in the cytoplasm. In response to stress, phosphorylates 'Ser-36' of histone H2B (H2BS36ph), leading to promote transcription. Acts as a key regulator of cell growth and proliferation by phosphorylating TSC2, RPTOR and ATG1/ULK1: in response to nutrient limitation, negatively regulates the mTORC1 complex by phosphorylating RPTOR component of the mTORC1 complex and by phosphorylating and activating TSC2. In response to nutrient limitation, promotes autophagy by phosphorylating and activating ATG1/ULK1. In that process also activates WDR45 (PubMed:28561066). In response to nutrient limitation, phosphorylates transcription factor FOXO3 promoting FOXO3 mitochondrial import (By similarity). AMPK also acts as a regulator of circadian rhythm by mediating phosphorylation of CRY1, leading to destabilize it. May regulate the Wnt signaling pathway by phosphorylating CTNNB1, leading to stabilize it. Also has tau-protein kinase activity: in response to amyloid beta A4 protein (APP) exposure, activated by CAMKK2, leading to phosphorylation of MAPT/TAU; however the relevance of such data remains unclear in vivo. Also phosphorylates CFTR, EEF2K, KLC1, NOS3 and SLC12A1.ACTIVITY REGULATION Activated by phosphorylation on Thr-183. Binding of AMP to non-catalytic gamma subunit (PRKAG1, PRKAG2 or PRKAG3) results in allosteric activation, inducing phosphorylation on Thr-183. AMP-binding to gamma subunit also sustains activity by preventing dephosphorylation of Thr-183. ADP also stimulates Thr-183 phosphorylation, without stimulating already phosphorylated AMPK. ATP promotes dephosphorylation of Thr-183, rendering the enzyme inactive. Under physiological conditions AMPK mainly exists in its inactive form in complex with ATP, which is much more abundant than AMP. AMPK is activated by antihyperglycemic drug metformin, a drug prescribed to patients with type 2 diabetes: in vivo, metformin seems to mainly inhibit liver gluconeogenesis. However, metformin can be used to activate AMPK in muscle and other cells in culture or ex vivo (PubMed:11602624). Selectively inhibited by compound C (6-[4-(2-Piperidin-1-yl-ethoxy)-phenyl)]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine. Activated by resveratrol, a natural polyphenol present in red wine, and S17834, a synthetic polyphenol.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.DOMAIN The AIS (autoinhibitory sequence) region shows some sequence similarity with the ubiquitin-associated domains and represses kinase activity.PTM Ubiquitinated.PTM Phosphorylated at Thr-183 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Also phosphorylated at Thr-183 by CAMKK2; triggered by a rise in intracellular calcium ions, without detectable changes in the AMP/ATP ratio. CAMKK1 can also phosphorylate Thr-183, but at a much lower level. Dephosphorylated by protein phosphatase 2A and 2C (PP2A and PP2C). Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK. Dephosphorylated by PPM1A and PPM1B.SIMILARITY Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily.UniProtQ13131183EQUAL1EQUAL559EQUALReactome Database ID Release 75380964Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380964ReactomeR-HSA-3809642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380964.2Reactome Database ID Release 75381844Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381844ReactomeR-HSA-3818441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381844.11Converted from EntitySet in ReactomeAMPK gammaReactome DB_ID: 381851PRKAG1AMPK gamma15'-AMP-activated protein kinase subunit gamma-1AAKG1_HUMANReactome DB_ID: 380946UniProt:P54619 PRKAG1PRKAG1FUNCTION AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.DOMAIN The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.DOMAIN The 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.PTM Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase gamma subunit family.UniProtP546191EQUAL331EQUALReactome Database ID Release 75380946Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380946ReactomeR-HSA-3809461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380946.1PRKAG2AMPK gamma2 (inactive)Reactome DB_ID: 200419UniProt:Q9UGJ0 PRKAG2PRKAG2FUNCTION AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.TISSUE SPECIFICITY Isoform B is ubiquitously expressed except in liver and thymus. The highest level is detected in heart with abundant expression in placenta and testis.DOMAIN The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.DOMAIN The 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.PTM Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase gamma subunit family.UniProtQ9UGJ01EQUAL569EQUALReactome Database ID Release 75200419Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200419ReactomeR-HSA-2004191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200419.1PRKAG3AMPK gamma35'-AMP-activated protein kinase subunit gamma-3AAKG3_HUMANReactome DB_ID: 381839UniProt:Q9UGI9 PRKAG3PRKAG3AMPKG3FUNCTION AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Gamma non-catalytic subunit mediates binding to AMP, ADP and ATP, leading to activate or inhibit AMPK: AMP-binding results in allosteric activation of alpha catalytic subunit (PRKAA1 or PRKAA2) both by inducing phosphorylation and preventing dephosphorylation of catalytic subunits. ADP also stimulates phosphorylation, without stimulating already phosphorylated catalytic subunit. ATP promotes dephosphorylation of catalytic subunit, rendering the AMPK enzyme inactive.SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2 (By similarity).TISSUE SPECIFICITY Skeletal muscle, with weak expression in heart and pancreas.DOMAIN The AMPK pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins of AMPK, except the presence of a non-phosphorylatable residue in place of Ser. In the absence of AMP this pseudosubstrate sequence may bind to the active site groove on the alpha subunit (PRKAA1 or PRKAA2), preventing phosphorylation by the upstream activating kinase STK11/LKB1.DOMAIN The 4 CBS domains mediate binding to nucleotides. Of the 4 potential nucleotide-binding sites, 3 are occupied, designated as sites 1, 3, and 4 based on the CBS modules that provide the acidic residue for coordination with the 2'- and 3'-hydroxyl groups of the ribose of AMP. Of these, site 4 appears to be a structural site that retains a tightly held AMP molecule (AMP 3). The 2 remaining sites, 1 and 3, can bind either AMP, ADP or ATP. Site 1 (AMP, ADP or ATP 1) is the high-affinity binding site and likely accommodates AMP or ADP. Site 3 (AMP, ADP or ATP 2) is the weakest nucleotide-binding site on the gamma subunit, yet it is exquisitely sensitive to changes in nucleotide levels and this allows AMPK to respond rapidly to changes in cellular energy status. Site 3 is likely to be responsible for protection of a conserved threonine in the activation loop of the alpha catalytic subunit through conformational changes induced by binding of AMP or ADP.PTM Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.POLYMORPHISM PRKAG3 genetic variants can be associated with increased glycogen content in skeletal muscle [MIM:604976]. Muscle fibers from carriers of variant Trp-225 have approximately 90% more muscle glycogen content than controls and decreased levels of intramuscular triglyceride.SIMILARITY Belongs to the 5'-AMP-activated protein kinase gamma subunit family.UniProtQ9UGI91EQUAL489EQUALReactome Database ID Release 75381839Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381839ReactomeR-HSA-3818391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381839.1Reactome Database ID Release 75381851Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381851ReactomeR-HSA-3818511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381851.11Converted from EntitySet in ReactomeAMPK betaReactome DB_ID: 381854PRKAB1AMPK beta15'-AMP-activated protein kinase subunit beta-1AAKB1_HUMANReactome DB_ID: 380968UniProt:Q9Y478 PRKAB1PRKAB1AMPKFUNCTION Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3). Interacts with FNIP1 and FNIP2.DOMAIN The glycogen-binding domain may target AMPK to glycogen so that other factors like glycogen-bound debranching enzyme or protein phosphatases can directly affect AMPK activity.PTM Phosphorylated when associated with the catalytic subunit (PRKAA1 or PRKAA2). Phosphorylated by ULK1; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase beta subunit family.UniProtQ9Y4782EQUAL270EQUALReactome Database ID Release 75380968Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380968ReactomeR-HSA-3809681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380968.1PRKAB2AMPK beta 2 (inactive)Reactome DB_ID: 200413UniProt:O43741 PRKAB2PRKAB2FUNCTION Non-catalytic subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. In response to reduction of intracellular ATP levels, AMPK activates energy-producing pathways and inhibits energy-consuming processes: inhibits protein, carbohydrate and lipid biosynthesis, as well as cell growth and proliferation. AMPK acts via direct phosphorylation of metabolic enzymes, and by longer-term effects via phosphorylation of transcription regulators. Also acts as a regulator of cellular polarity by remodeling the actin cytoskeleton; probably by indirectly activating myosin. Beta non-catalytic subunit acts as a scaffold on which the AMPK complex assembles, via its C-terminus that bridges alpha (PRKAA1 or PRKAA2) and gamma subunits (PRKAG1, PRKAG2 or PRKAG3).SUBUNIT AMPK is a heterotrimer of an alpha catalytic subunit (PRKAA1 or PRKAA2), a beta (PRKAB1 or PRKAB2) and a gamma non-catalytic subunits (PRKAG1, PRKAG2 or PRKAG3).PTM Phosphorylated when associated with the catalytic subunit (PRKAA1 or PRKAA2). Phosphorylated by ULK1 and ULK2; leading to negatively regulate AMPK activity and suggesting the existence of a regulatory feedback loop between ULK1, ULK2 and AMPK.SIMILARITY Belongs to the 5'-AMP-activated protein kinase beta subunit family.UniProtO437411EQUAL272EQUALReactome Database ID Release 75200413Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=200413ReactomeR-HSA-2004131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-200413.1Reactome Database ID Release 75381854Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381854ReactomeR-HSA-3818541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-381854.11Reactome Database ID Release 75380934Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380934ReactomeR-HSA-3809341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380934.11Reactome Database ID Release 75380931Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380931ReactomeR-HSA-3809311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380931.1GENE ONTOLOGYGO:0004679Reactome Database ID Release 75381847Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=381847Reactome Database ID Release 75380927Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380927ReactomeR-HSA-3809273Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380927.317386266Pubmed2007PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinaseSancak, YThoreen, CCPeterson, TRLindquist, RAKang, SASpooner, ECarr, SASabatini, DMMol Cell 25:903-1517277771Pubmed2007Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40Vander Haar, ELee, SIBandhakavi, SGriffin, TJKim, DHNat Cell Biol 9:316-2314651849Pubmed2003TSC2 mediates cellular energy response to control cell growth and survivalInoki, KZhu, TGuan, KLCell 115:577-90LEFT-TO-RIGHT3.6.5.43.6.5.33.6.5.23.6.5.1RHEB in mTORC1:RHEB:GTP hydrolyses GTPTSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of the small G-protein Rheb. This results in the conversion of Rheb:GTP to Rheb:GDP. GDP-bound Rheb is unable to activate mTOR (Inoki et al. 2003, Tee et al. 2003). It is not demonstrated that RHEB hydrolyzes GTP when present in the mTORC1 complex; given the low affinity of RHEB for mTOR, it may dissociate from the mTORC1 complex before TSC2 stimulates hydrolysis of GTP; TSC2 may not have access to critical residues of RHEB when present inside mTORC1.Authored: Katajisto, P, Makela, T, Wu, J, 2008-11-19Reviewed: Zwartkruis, Fried J T, 2015-05-14Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Jassal, B, 2008-11-19 15:14:38Active mTORC1 complexmTORC1:Ragulator:Rag:GNP:RHEB:GTPReactome DB_ID: 165678lysosomal membraneGENE ONTOLOGYGO:0005765RHEB:GTPReactome DB_ID: 165189GTPGuanosine 5'-triphosphateReactome DB_ID: 29438GTP [ChEBI:15996]GTPGuanosine 5'-triphosphateChEBICHEBI:15996Reactome Database ID Release 7529438Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29438ReactomeR-ALL-294383Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29438.3COMPOUNDC000441RHEBRhebReactome DB_ID: 165190UniProt:Q15382 RHEBRHEBRHEB2FUNCTION Activates the protein kinase activity of mTORC1, and thereby plays a role in the regulation of apoptosis. Stimulates the phosphorylation of S6K1 and EIF4EBP1 through activation of mTORC1 signaling. Has low intrinsic GTPase activity.ACTIVITY REGULATION Alternates between an inactive form bound to GDP and an active form bound to GTP. Inactivated by TSC1-TSC2 via the GTPase activating protein (GAP) domain of TSC2.SUBUNIT Binds to mTORC1 in a guanyl nucleotide-independent manner. Interacts directly with MTOR, MLST8 and RPTOR. Interacts with TSC2. Interacts (when prenylated) with PDE6D; this promotes release from membranes.TISSUE SPECIFICITY Ubiquitous. Highest levels observed in skeletal and cardiac muscle.PTM Farnesylation is important for efficiently activating mTORC1-mediated signaling.PTM Phosphorylation by MAPKAPK5 impairs GTP-binding and inactivation.MISCELLANEOUS The conserved catalytic Gln-64 found in other Ras-like GTPases seems not to be involved in GTP hydrolysis in RHEB.SIMILARITY Belongs to the small GTPase superfamily. Rheb family.UniProtQ153821EQUAL181EQUALReactome Database ID Release 75165190Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165190ReactomeR-HSA-1651901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165190.11Reactome Database ID Release 75165189Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165189ReactomeR-HSA-1651891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165189.11Ragulator:Rag:GNP heterodimers:mTORC1mTORC1:Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9Reactome DB_ID: 5653972mTORC1MLST8:MTOR:RPTORmLST8:mTOR:RaptorReactome DB_ID: 377400RPTORRegulatory-associated protein of mTORRPTOR_HUMANReactome DB_ID: 3006727UniProt:Q8N122 RPTORRPTORKIAA1303RAPTORFUNCTION Involved in the control of the mammalian target of rapamycin complex 1 (mTORC1) activity which regulates cell growth and survival, and autophagy in response to nutrient and hormonal signals; functions as a scaffold for recruiting mTORC1 substrates. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Involved in ciliogenesis.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR (PubMed:12150925, PubMed:12408816, PubMed:17386266, PubMed:25940091). mTORC1 binds to and is inhibited by FKBP12-rapamycin (PubMed:12408816, PubMed:15066126). Binds directly to 4EBP1 and RPS6KB1 independently of its association with MTOR (PubMed:12150925, PubMed:12150926). Binds preferentially to poorly or non-phosphorylated forms of EIF4EBP1, and this binding is critical to the ability of MTOR to catalyze phosphorylation (PubMed:12747827). Forms a complex with MTOR under both leucine-rich and -poor conditions. Interacts with ULK1 in a nutrient-dependent manner; the interaction is reduced during starvation (PubMed:19211835). Interacts (when phosphorylated by AMPK) with 14-3-3 protein, leading to inhibition of its activity (PubMed:18439900). Interacts with SPAG5; SPAG5 competes with MTOR for RPTOR-binding, resulting in decreased mTORC1 formation. Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with G3BP1. The complex formed with G3BP1 AND SPAG5 is increased by oxidative stress (PubMed:23953116). Interacts with HTR6 (PubMed:23027611). Interacts with PIH1D1 (PubMed:24036451). Interacts with LARP1 (PubMed:25940091). Interacts with BRAT1 (PubMed:25657994). Interacts with SIK3 (PubMed:30232230).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein F17; this interaction dysregulates mTOR.TISSUE SPECIFICITY Highly expressed in skeletal muscle, and in a lesser extent in brain, lung, small intestine, kidney and placenta. Isoform 3 is widely expressed, with highest levels in nasal mucosa and pituitary and lowest in spleen.PTM Insulin-stimulated phosphorylation at Ser-863 by MTOR and MAPK8 up-regulates mTORC1 activity. Osmotic stress also induces phosphorylation at Ser-696, Thr-706 and Ser-863 by MAPK8. Ser-863 phosphorylation is required for phosphorylation at Ser-855 and Ser-859. In response to nutrient limitation, phosphorylated by AMPK; phosphorylation promotes interaction with 14-3-3 proteins, leading to negative regulation of the mTORC1 complex. In response to growth factors, phosphorylated at Ser-719, Ser-721 and Ser-722 by RPS6KA1, which stimulates mTORC1 activity.SIMILARITY Belongs to the WD repeat RAPTOR family.UniProtQ8N1221EQUAL1335EQUALReactome Database ID Release 753006727Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3006727ReactomeR-HSA-30067271Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3006727.11MLST8mLst8Reactome DB_ID: 165676UniProt:Q9BVC4 MLST8MLST8GBLLST8FUNCTION Subunit of both mTORC1 and mTORC2, which regulates cell growth and survival in response to nutrient and hormonal signals. mTORC1 is activated in response to growth factors or amino acids. Growth factor-stimulated mTORC1 activation involves a AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase that potently activates the protein kinase activity of mTORC1. Amino acid-signaling to mTORC1 requires its relocalization to the lysosomes mediated by the Ragulator complex and the Rag GTPases. Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. mTORC1 phosphorylates EIF4EBP1 and releases it from inhibiting the elongation initiation factor 4E (eiF4E). mTORC1 phosphorylates and activates S6K1 at 'Thr-389', which then promotes protein synthesis by phosphorylating PDCD4 and targeting it for degradation. Within mTORC1, LST8 interacts directly with MTOR and enhances its kinase activity. In nutrient-poor conditions, stabilizes the MTOR-RPTOR interaction and favors RPTOR-mediated inhibition of MTOR activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. mTORC2 seems to function upstream of Rho GTPases to regulate the actin cytoskeleton, probably by activating one or more Rho-type guanine nucleotide exchange factors. mTORC2 promotes the serum-induced formation of stress-fibers or F-actin. mTORC2 plays a critical role in AKT1 'Ser-473' phosphorylation, which may facilitate the phosphorylation of the activation loop of AKT1 on 'Thr-308' by PDK1 which is a prerequisite for full activation. mTORC2 regulates the phosphorylation of SGK1 at 'Ser-422'. mTORC2 also modulates the phosphorylation of PRKCA on 'Ser-657'.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. mTORC1 binds to and is inhibited by FKBP12-rapamycin. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Contrary to mTORC1, mTORC2 does not bind to and is not sensitive to FKBP12-rapamycin. Interacts directly with MTOR and RPTOR. Interacts with RHEB. Interacts with MEAK7 (PubMed:29750193). Interacts with SIK3 (PubMed:30232230).TISSUE SPECIFICITY Broadly expressed, with highest levels in skeletal muscle, heart and kidney.SIMILARITY Belongs to the WD repeat LST8 family.UniProtQ9BVC41EQUAL326EQUALReactome Database ID Release 75165676Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165676ReactomeR-HSA-1656761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165676.11MTORmTORReactome DB_ID: 165662UniProt:P42345 MTORMTORFRAPFRAP1FRAP2RAFT1RAPT1FUNCTION Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18925875, PubMed:18497260, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (By similarity). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12150925, PubMed:12087098, PubMed:18925875). This also includes mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3: in the presence of nutrients, mediates phosphorylation of TFEB and TFE3, promoting their cytosolic retention and inactivation (PubMed:22576015, PubMed:22343943, PubMed:22692423). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22576015, PubMed:22343943, PubMed:22692423). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429704, PubMed:23429703). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (By similarity). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). mTORC1 also negatively regulates autophagy through phosphorylation of ULK1 (By similarity). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (By similarity). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity). Phosphorylates SQSTM1, promoting interaction between SQSTM1 and KEAP1 and subsequent inactivation of the BCR(KEAP1) complex (By similarity).ACTIVITY REGULATION Activation of mTORC1 by growth factors such as insulin involves AKT1-mediated phosphorylation of TSC1-TSC2, which leads to the activation of the RHEB GTPase a potent activator of the protein kinase activity of mTORC1. Insulin-stimulated and amino acid-dependent phosphorylation at Ser-1261 promotes autophosphorylation and the activation of mTORC1. Activation by amino acids requires relocalization of the mTORC1 complex to lysosomes that is mediated by the Ragulator complex, SLC38A9, and the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD (PubMed:18497260, PubMed:20381137, PubMed:25561175, PubMed:25567906). On the other hand, low cellular energy levels can inhibit mTORC1 through activation of PRKAA1 while hypoxia inhibits mTORC1 through a REDD1-dependent mechanism which may also require PRKAA1. The kinase activity of MTOR within the mTORC1 complex is positively regulated by MLST8 and negatively regulated by DEPTOR and AKT1S1. MTOR phosphorylates RPTOR which in turn inhibits mTORC1. MTOR is the target of the immunosuppressive and anti-cancer drug rapamycin which acts in complex with FKBP1A/FKBP12, and specifically inhibits its kinase activity. mTORC2 is also activated by growth factors, but seems to be nutrient-insensitive. It may be regulated by RHEB but in an indirect manner through the PI3K signaling pathway.SUBUNIT Part of the mammalian target of rapamycin complex 1 (mTORC1) which contains MTOR, MLST8, RPTOR, AKT1S1/PRAS40 and DEPTOR. The mTORC1 complex is a 1 Md obligate dimer of two stoichiometric heterotetramers with overall dimensions of 290 A x 210 A x 135 A. It has a rhomboid shape and a central cavity, the dimeric interfaces are formed by interlocking interactions between the two MTOR and the two RPTOR subunits. The MLST8 subunit forms distal foot-like protuberances, and contacts only one MTOR within the complex, while the small PRAS40 localizes to the midsection of the central core, in close proximity to RPTOR. Part of the mammalian target of rapamycin complex 2 (mTORC2) which contains MTOR, MLST8, PRR5, RICTOR, MAPKAP1 and DEPTOR. Interacts with PLPP7 and PML. Interacts with PRR5 and RICTOR; the interaction is direct within the mTORC2 complex. Interacts with WAC; WAC positively regulates MTOR activity by promoting the assembly of the TTT complex composed of TELO2, TTI1 and TTI2 and the RUVBL complex composed of RUVBL1 and RUVBL2 into the TTT-RUVBL complex which leads to the dimerization of the mTORC1 complex and its subsequent activation (PubMed:26812014). Interacts with UBQLN1. Interacts with TTI1 and TELO2. Interacts with CLIP1; phosphorylates and regulates CLIP1. Interacts with NBN. Interacts with HTR6 (PubMed:23027611). Interacts with BRAT1. Interacts with MEAK7 (via C-terminal domain); the interaction increases upon nutrient stimulation (PubMed:29750193). Interacts with TM4SF5; the interaction is positively regulated by arginine and is negatively regulated by leucine (PubMed:30956113). Interacts with GPR137B (PubMed:31036939).TISSUE SPECIFICITY Expressed in numerous tissues, with highest levels in testis.DOMAIN The kinase domain (PI3K/PI4K) is intrinsically active but has a highly restricted catalytic center.DOMAIN The FAT domain forms three discontinuous subdomains of alpha-helical TPR repeats plus a single subdomain of HEAT repeats. The four domains pack sequentially to form a C-shaped a-solenoid that clamps onto the kinase domain (PubMed:23636326).PTM Autophosphorylates when part of mTORC1 or mTORC2. Phosphorylation at Ser-1261, Ser-2159 and Thr-2164 promotes autophosphorylation. Phosphorylation in the kinase domain modulates the interactions of MTOR with RPTOR and PRAS40 and leads to increased intrinsic mTORC1 kinase activity. Phosphorylation at Thr-2173 in the ATP-binding region by AKT1 strongly reduces kinase activity.SIMILARITY Belongs to the PI3/PI4-kinase family.UniProtP423451EQUAL2549EQUALReactome Database ID Release 75165662Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165662ReactomeR-HSA-1656621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165662.11Reactome Database ID Release 75377400Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377400ReactomeR-HSA-3774001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377400.1ComplexPortalCPX-5031Ragulator:RagA,B:GTP:RagC,D:GDP:SLC38A9Reactome DB_ID: 8952725Ragulator:RagA,B:GTP:RagC,D:GDPReactome DB_ID: 5653979RagA,B:GTP:RagC,D:GDPReactome DB_ID: 5653945Converted from EntitySet in ReactomeRRAGC,RRAGD:GDPReactome DB_ID: 5653964RRAGC:GDPReactome DB_ID: 5653973RRAGCRas-related GTP-binding protein CRRAGC_HUMANReactome DB_ID: 5653949UniProt:Q9HB90 RRAGCRRAGCFUNCTION Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:20381137, PubMed:27234373, PubMed:24095279). Forms heterodimeric Rag complexes with RRAGA or RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form (PubMed:24095279). In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:27234373, PubMed:24095279). This is a crucial step in the activation of the TOR signaling cascade by amino acids (PubMed:20381137, PubMed:27234373, PubMed:24095279).ACTIVITY REGULATION In high-amino acid conditions, activated by GTPase activating protein (GAP) FLCN that stimulates RRAGC GTPase activity to turn it into its active GDP-bound form.SUBUNIT Forms a heterodimer with RRAGA, in a sequence-independent manner, and RRAGB (PubMed:11073942, PubMed:14660641). Heterodimerization stabilizes proteins of the heterodimer (PubMed:11073942). In complex with RRAGA or RRAGB, interacts with RPTOR; this interaction is particularly efficient with GTP-loaded RRAGB and GDP-loaded RRAGC (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with NOL8 (PubMed:14660641). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGB, is negatively regulated by amino acids and prevents interaction with RPTOR (PubMed:22575674). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925). Interacts with PIP4P1 (By similarity).DISEASE RRAGC mutations have been found in a patient with idiopathic dilated cardiomyopathy with ventricular dilation and systolic dysfunction, bilateral cataracts, and mild facial dysmorphisms.SIMILARITY Belongs to the GTR/RAG GTP-binding protein family.UniProtQ9HB902EQUAL399EQUALReactome Database ID Release 755653949Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653949ReactomeR-HSA-56539491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653949.11GDPGuanosine 5'-diphosphateGuanosine diphosphateReactome DB_ID: 29420GDP [ChEBI:17552]GDPGuanosine 5'-diphosphateGuanosine diphosphateChEBICHEBI:17552Reactome Database ID Release 7529420Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29420ReactomeR-ALL-294202Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29420.2COMPOUNDC000351Reactome Database ID Release 755653973Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653973ReactomeR-HSA-56539732Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653973.2RRAGD:GDPReactome DB_ID: 56539701RRAGDRas-related GTP-binding protein DRRAGD_HUMANReactome DB_ID: 5653953UniProt:Q9NQL2 RRAGDRRAGDFUNCTION Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:20381137, PubMed:24095279). Forms heterodimeric Rag complexes with RRAGA or RRAGB and cycles between an inactive GTP-bound and an active GDP-bound form (PubMed:24095279). In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:24095279). This is a crucial step in the activation of the TOR signaling cascade by amino acids (PubMed:20381137, PubMed:24095279).ACTIVITY REGULATION In high-amino acid conditions, activated by GTPase activating protein (GAP) FLCN that stimulates RRAGD GTPase activity to turn it into its active GDP-bound form.SUBUNIT Forms a heterodimer with RRAGA in a sequence-independent manner and RRAGB (PubMed:11073942, PubMed:14660641). Heterodimerization stabilizes RRAG proteins (PubMed:11073942, PubMed:14660641, PubMed:25561175, PubMed:25567906). In complex with RRAGB, interacts with RPTOR; this interaction is particularly efficient with GTP-loaded RRAGB and GDP-loaded RRAGC (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (By similarity). Interacts with NOL8 (PubMed:14660641). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGD and is negatively regulated by amino acids (PubMed:22575674). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925).SIMILARITY Belongs to the GTR/RAG GTP-binding protein family.UniProtQ9NQL21EQUAL400EQUALReactome Database ID Release 755653953Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653953ReactomeR-HSA-56539531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653953.11Reactome Database ID Release 755653970Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653970ReactomeR-HSA-56539701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653970.1Reactome Database ID Release 755653964Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653964ReactomeR-HSA-56539642Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653964.21Converted from EntitySet in ReactomeRRAGA, RRAGB:GTPReactome DB_ID: 5653946RRAGA:GTPReactome DB_ID: 56539781RRAGARas-related GTP-binding protein ARRAGA_HUMANReactome DB_ID: 5653577UniProt:Q7L523 RRAGARRAGAFUNCTION Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:20381137, PubMed:24095279, PubMed:25936802). Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form (PubMed:20381137, PubMed:24095279, PubMed:25936802). In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:20381137, PubMed:25936802). Involved in the RCC1/Ran-GTPase pathway (PubMed:9394008). May play a direct role in a TNF-alpha signaling pathway leading to induction of cell death (PubMed:8995684).FUNCTION (Microbial infection) May alternatively act as a cellular target for adenovirus E3-14.7K, an inhibitor of TNF-alpha functions, thereby affecting cell death.ACTIVITY REGULATION The activation of GTP-binding proteins is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP) (PubMed:25936802). The GATOR1 complex functions as a GAP and stimulates RRAGA GTPase activity to turn it into its inactive GDP-bound form (PubMed:25936802, PubMed:23723238).SUBUNIT Can occur as a homodimer or as a heterodimer with RRAGC or RRAGD in a sequence-independent manner; heterodimerization stabilizes proteins of the heterodimer (PubMed:11073942, PubMed:20381137). In complex with RRAGC, but not with RRAGB, interacts with RPTOR (PubMed:18497260). The GTP-bound form of RRAGA interacts with NOL8 (PubMed:14660641). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGA and is negatively regulated by amino acids (PubMed:22575674). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts (inactive GDP-bound form) with RNF152; stimulated by amino acid starvation (PubMed:25936802). Interacts (polyubiquitinated) with the GATOR1 complex; inactivates RRAGA (PubMed:25936802). Interacts (polyubiquitinated) with TSC2 (PubMed:25936802). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925). Interacts with PIP4P1 (By similarity). Interacts with GPR137B (PubMed:31036939).SUBUNIT (Microbial infection) Interacts with adenovirus E3 14.7 kDa protein.TISSUE SPECIFICITY Ubiquitously expressed with highest levels of expression in skeletal muscle, heart, and brain.PTM Ubiquitinated. 'Lys-68'-linked polyubiquitination of the GDP-bound inactive form of RRAGA by RNF152 is increased in response to amino acid starvation. Polyubiquitination promotes interaction with the GATOR1 complex. This does not affect RRAGA degradation.SIMILARITY Belongs to the GTR/RAG GTP-binding protein family.UniProtQ7L5231EQUAL313EQUALReactome Database ID Release 755653577Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653577ReactomeR-HSA-56535771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653577.11Reactome Database ID Release 755653978Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653978ReactomeR-HSA-56539781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653978.1RRAGB:GTPReactome DB_ID: 5653976RRAGBRas-related GTP-binding protein BRRAGB_HUMANReactome DB_ID: 5653579UniProt:Q5VZM2 RRAGBRRAGBFUNCTION Guanine nucleotide-binding protein that plays a crucial role in the cellular response to amino acid availability through regulation of the mTORC1 signaling cascade (PubMed:18497260, PubMed:20381137, PubMed:24095279, PubMed:23723238). Forms heterodimeric Rag complexes with RRAGC or RRAGD and cycles between an inactive GDP-bound and an active GTP-bound form (PubMed:18497260, PubMed:20381137, PubMed:24095279, PubMed:23723238). In its active form participates in the relocalization of mTORC1 to the lysosomes and its subsequent activation by the GTPase RHEB (PubMed:18497260, PubMed:20381137, PubMed:23723238). Involved in the RCC1/Ran-GTPase pathway (PubMed:9394008).ACTIVITY REGULATION The activation of GTP-binding proteins is generally mediated by a guanine exchange factor (GEF), while inactivation through hydrolysis of bound GTP is catalyzed by a GTPase activating protein (GAP). The GATOR1 complex functions as a GAP and stimulates RRAGB GTPase activity to turn it into its inactive GDP-bound form.SUBUNIT Interacts with RRAGC and RRAGD; heterodimerization stabilizes RRAG proteins (PubMed:11073942). In complex with RRAGC, but not with RRAGA, interacts with RPTOR; this interaction is particularly efficient with GTP-loaded RRAGB and GDP-loaded RRAGC (PubMed:18497260). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (By similarity). Interacts with SH3BP4; the interaction with this negative regulator is most probably direct, preferentially occurs with the inactive GDP-bound form of RRAGB, is negatively regulated by amino acids and prevents interaction with RPTOR (PubMed:22575674). Interacts with the GATOR1 complex; inactivates RRAGB (PubMed:23723238). The Rag heterodimer interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with SESN1, SESN2 and SESN3 (PubMed:25259925).SIMILARITY Belongs to the GTR/RAG GTP-binding protein family.UniProtQ5VZM21EQUAL374EQUALReactome Database ID Release 755653579Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653579ReactomeR-HSA-56535791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653579.111Reactome Database ID Release 755653976Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653976ReactomeR-HSA-56539761Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653976.1Reactome Database ID Release 755653946Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653946ReactomeR-HSA-56539462Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653946.21Reactome Database ID Release 755653945Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653945ReactomeR-HSA-56539452Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653945.21RagulatorReactome DB_ID: 5653921LAMTOR1Ragulator complex protein LAMTOR1LTOR1_HUMANReactome DB_ID: 5653582UniProt:Q6IAA8 LAMTOR1LAMTOR1C11orf59PDROPP7157FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. LAMTOR1 is directly responsible for anchoring the Ragulator complex to membranes. Also required for late endosomes/lysosomes biogenesis it may regulate both the recycling of receptors through endosomes and the MAPK signaling pathway through recruitment of some of its components to late endosomes. May be involved in cholesterol homeostasis regulating LDL uptake and cholesterol release from late endosomes/lysosomes. May also play a role in RHOA activation.SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR2 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with RRAGB and RRAGD; the interaction is direct indicating that it probably constitutes the main RAG-interacting subunit of the Ragulator complex (PubMed:22980980). Interacts with MMP14 (PubMed:19654316). Interacts with CDKN1B; prevents the interaction of CDKN1B with RHOA leaving RHOA in a form accessible to activation by ARHGEF2 (PubMed:19654316). Interacts with PIP4P1 (PubMed:29644770).INDUCTION Down-regulated by cholesterol (at protein level).SIMILARITY Belongs to the LAMTOR1 family.UniProtQ6IAA82EQUAL161EQUALReactome Database ID Release 755653582Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653582ReactomeR-HSA-56535821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653582.11LAMTOR5Ragulator complex protein LAMTOR5LTOR5_HUMANReactome DB_ID: 5655441UniProt:O43504 LAMTOR5LAMTOR5HBXIPXIPFUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. When complexed to BIRC5, interferes with apoptosome assembly, preventing recruitment of pro-caspase-9 to oligomerized APAF1, thereby selectively suppressing apoptosis initiated via the mitochondrial/cytochrome c pathway. Down-regulates hepatitis B virus (HBV) replication.SUBUNIT Homodimer (PubMed:21059355). Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5. LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with phosphorylated BIRC5; the resulting complex binds pro-caspase-9, as well as active caspase-9, but much less efficiently (PubMed:12773388). Interacts with SUPV3L1 (PubMed:16176273).SUBUNIT (Microbial infection) Interacts with hepatitis B virus (HBV) oncoprotein HBX C-terminus.TISSUE SPECIFICITY Highly expressed in skeletal and cardiac muscle, followed by pancreas, kidney, liver, brain, placenta and lung. Elevated levels in both cancerous and non-cancerous liver tissue of patients with chronic HBV infection compared with hepatic tissue without HBV infection.MISCELLANEOUS Suppression of caspase activation by the BIRC5/HBXIP complex is increased in the presence of HBX.SIMILARITY Belongs to the LAMTOR5 family.UniProtO435041EQUAL91EQUALReactome Database ID Release 755655441Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5655441ReactomeR-HSA-56554411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5655441.11LAMTOR4Ragulator complex protein LAMTOR4LTOR4_HUMANReactome DB_ID: 5655432UniProt:Q0VGL1 LAMTOR4LAMTOR4C7orf59FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated.SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913).SIMILARITY Belongs to the LAMTOR4 family.UniProtQ0VGL11EQUAL99EQUALReactome Database ID Release 755655432Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5655432ReactomeR-HSA-56554321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5655432.11LAMTOR2Ragulator complex protein LAMTOR2LTOR2_HUMANReactome DB_ID: 5653583UniProt:Q9Y2Q5 LAMTOR2LAMTOR2MAPBPIPROBLD3HSPC003FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR1 and LAMTOR3; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Interacts with MAPK1 and MAP2K1 (By similarity). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913).SIMILARITY Belongs to the GAMAD family.UniProtQ9Y2Q51EQUAL125EQUALReactome Database ID Release 755653583Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653583ReactomeR-HSA-56535831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653583.11LAMTOR3Ragulator complex protein LAMTOR3LTOR3_HUMANReactome DB_ID: 5653581UniProt:Q9UHA4 LAMTOR3LAMTOR3MAP2K1IP1MAPKSP1PRO2783FUNCTION As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator functions as a guanine nucleotide exchange factor activating the small GTPases Rag. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.SUBUNIT Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5 (PubMed:20381137, PubMed:22980980). LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer (PubMed:20381137, PubMed:22980980). Interacts with LAMTOR1 and LAMTOR2; the interaction is direct (PubMed:20381137, PubMed:22980980). The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RRAGA, RRAGB, RRAGC and RRAGD; regulated by amino acid availability (PubMed:20381137). The Ragulator complex interacts with SLC38A9; the probable amino acid sensor (PubMed:25561175, PubMed:25567906). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RRAGA/RagA or RRAGB/RagB GDP-bound, RRAGC/RagC or RRAGD/RagD GTP-bound, and Ragulator (PubMed:31704029, PubMed:31672913). Interacts with MAP2K1/MEK1 and MAPK2 (By similarity). Interacts with MORG1 (By similarity).SIMILARITY Belongs to the LAMTOR3 family.UniProtQ9UHA41EQUAL124EQUALReactome Database ID Release 755653581Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653581ReactomeR-HSA-56535811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653581.11Reactome Database ID Release 755653921Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653921ReactomeR-HSA-56539211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653921.1ComplexPortalCPX-47411Reactome Database ID Release 755653979Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653979ReactomeR-HSA-56539792Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653979.21SLC38A9Putative sodium-coupled neutral amino acid transporter 9S38A9_HUMANReactome DB_ID: 5215938UniProt:Q8NBW4 SLC38A9SLC38A9URLC11FUNCTION Lysosomal amino acid transporter involved in the activation of mTORC1 in response to amino acid levels. Probably acts as an amino acid sensor of the Rag GTPases and Ragulator complexes, 2 complexes involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids (PubMed:25561175, PubMed:25567906, PubMed:29053970). Following activation by amino acids, the Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. SLC38A9 mediates transport of amino acids with low capacity and specificity with a slight preference for polar amino acids (PubMed:25561175, PubMed:25567906). Acts as an arginine sensor (PubMed:25567906, PubMed:29053970). Following activation by arginine binding, mediates transport of leucine, tyrosine and phenylalanine with high efficiency, and is required for the efficient utilization of these amino acids after lysosomal protein degradation (PubMed:29053970).ACTIVITY REGULATION Amino acid transport is sodium-dependent (By similarity). Transport of leucine, tyrosine and phenylalanine is increased by arginine binding (PubMed:29053970).SUBUNIT Associated component of the Ragulator complex (composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5). Associated component of the Rag GTPases heterodimers (composed of RRAGA, RRAGB, RRAGC and RRAGD). Interacts with TM4SF5 (PubMed:30956113).DOMAIN The cytosolic N-terminus part of the protein mediates interaction with the Ragulator complex and the Rag GTPases heterodimers.PTM Glycosylated.SIMILARITY Belongs to the amino acid/polyamine transporter 2 family. SLC38A9 subfamily.UniProtQ8NBW41EQUAL561EQUALReactome Database ID Release 755215938Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5215938ReactomeR-HSA-52159381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5215938.11Reactome Database ID Release 758952725Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=8952725ReactomeR-HSA-89527253Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-8952725.31Reactome Database ID Release 755653972Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5653972ReactomeR-HSA-56539723Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5653972.31Reactome Database ID Release 75165678Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165678ReactomeR-HSA-1656781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165678.1mTORC1:Ragulator:Rag:GNP:RHEB:GDPReactome DB_ID: 5693447RHEB:GDPReactome DB_ID: 16519111Reactome Database ID Release 75165191Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165191ReactomeR-HSA-1651911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165191.111Reactome Database ID Release 755693447Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5693447ReactomeR-HSA-56934471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5693447.1ACTIVATIONactiveUnit: #Protein44GENE ONTOLOGYGO:0003924Reactome Database ID Release 755673773Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5673773Reactome Database ID Release 75380979Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380979ReactomeR-HSA-3809793Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380979.312869586Pubmed2003Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signalingInoki, KLi, YXu, TGuan, KLGenes Dev 17:1829-3412906785Pubmed2003Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward RhebTee, ARManning, BDRoux, PPCantley, Lewis CBlenis, JCurr Biol 13:1259-6812820960Pubmed2003Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2Garami, AttilaZwartkruis, Fried J TNobukuni, TakahiroJoaquin, ManelRoccio, MartaStocker, HugoKozma, Sara CHafen, ErnstBos, Johannes LThomas, GeorgeMol. Cell 11:1457-66ACTIVATIONReactome Database ID Release 755673774Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5673774ReactomeR-HSA-56737741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5673774.1LEFT-TO-RIGHTSESN1,2,3 bind AMPKSESN1, SESN2 and possibly SESN3 are able to bind the AMPK complex and increase its catalytic activity. The exact mechanism has not been elucidated, but recent studies suggest that sestrin-bound AMPK is resistant to inactivation through AKT-induced dephosphorylation (Budanov and Karin 2008, Sanli et al. 2012, Cam et al. 2014).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23SESN1,2,3:p-AMPK heterotrimer:AMPReactome DB_ID: 563193911Reactome Database ID Release 755631939Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5631939ReactomeR-HSA-56319391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5631939.1Reactome Database ID Release 755631941Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5631941ReactomeR-HSA-56319413Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5631941.318692468Pubmed2008p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signalingBudanov, Andrei VKarin, MCell 134:451-6024366874Pubmed2014p53/TAp63 and AKT regulate mammalian target of rapamycin complex 1 (mTORC1) signaling through two independent parallel pathways in the presence of DNA damageCam, MarenBid, Hemant KXiao, LinlinZambetti, Gerard PHoughton, Peter JCam, HakanJ. Biol. Chem. 289:4083-9422363791Pubmed2012Sestrin2 modulates AMPK subunit expression and its response to ionizing radiation in breast cancer cellsSanli, ToranLinher-Melville, KatjaTsakiridis, TheodorosSingh, GurmitPLoS ONE 7:e32035LEFT-TO-RIGHTTP63/TP53 bind the DDIT4 gene promoterDDIT4 (REDD1) gene has a p53 response element immediately upstream of the transcription start site, and this p53 response element is able to bind both TP63 and TP53 transcription factors (Ellisen et al. 2002).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23Converted from EntitySet in Reactomep63 tetramer/p53 tetramerTP63 Tetramer/ TP53 TetramerReactome DB_ID: 5632387p63 tetramerTP63 TetramerReactome DB_ID: 5632381TP63Tumor protein 63P63_HUMANReactome DB_ID: 2997585UniProt:Q9H3D4 TP63TP63KETP63P73HP73LTP73LFUNCTION Acts as a sequence specific DNA binding transcriptional activator or repressor. The isoforms contain a varying set of transactivation and auto-regulating transactivation inhibiting domains thus showing an isoform specific activity. Isoform 2 activates RIPK4 transcription. May be required in conjunction with TP73/p73 for initiation of p53/TP53 dependent apoptosis in response to genotoxic insults and the presence of activated oncogenes. Involved in Notch signaling by probably inducing JAG1 and JAG2. Plays a role in the regulation of epithelial morphogenesis. The ratio of DeltaN-type and TA*-type isoforms may govern the maintenance of epithelial stem cell compartments and regulate the initiation of epithelial stratification from the undifferentiated embryonal ectoderm. Required for limb formation from the apical ectodermal ridge. Activates transcription of the p21 promoter.SUBUNIT Binds DNA as a homotetramer. Isoform composition of the tetramer may determine transactivation activity. Isoforms Alpha and Gamma interact with HIPK2. Interacts with SSRP1, leading to stimulate coactivator activity. Isoform 1 and isoform 2 interact with WWP1. Interacts with PDS5A. Isoform 5 (via activation domain) interacts with NOC2L.TISSUE SPECIFICITY Widely expressed, notably in heart, kidney, placenta, prostate, skeletal muscle, testis and thymus, although the precise isoform varies according to tissue type. Progenitor cell layers of skin, breast, eye and prostate express high levels of DeltaN-type isoforms. Isoform 10 is predominantly expressed in skin squamous cell carcinomas, but not in normal skin tissues.DOMAIN The transactivation inhibitory domain (TID) can interact with, and inhibit the activity of the N-terminal transcriptional activation domain of TA*-type isoforms.PTM May be sumoylated.PTM Ubiquitinated. Polyubiquitination involves WWP1 and leads to proteasomal degradation of this protein.DISEASE Defects in TP63 are a cause of cervical, colon, head and neck, lung and ovarian cancers.SIMILARITY Belongs to the p53 family.UniProtQ9H3D41EQUAL680EQUALReactome Database ID Release 752997585Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997585ReactomeR-HSA-29975851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2997585.14Reactome Database ID Release 755632381Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632381ReactomeR-HSA-56323812Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632381.2Reactome Database ID Release 755632387Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632387ReactomeR-HSA-56323871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632387.1DDIT4 GeneREDD1 GeneReactome DB_ID: 5632378ENSEMBL:ENSG00000168209 DDIT4DDIT4REDD1RTP801ENSEMBLENSG00000168209Reactome Database ID Release 755632378Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632378ReactomeR-HSA-56323781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632378.1TP63/T53:DDIT4 GeneReactome DB_ID: 563239211Reactome Database ID Release 755632392Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632392ReactomeR-HSA-56323921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632392.1Reactome Database ID Release 755632393Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632393ReactomeR-HSA-56323933Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632393.312453409Pubmed2002REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen speciesEllisen, Leif WRamsayer, Kate DJohannessen, Cory MYang, AnnieBeppu, HideyukiMinda, KarolinaOliner, Jonathan DMcKeon, FrankHaber, Daniel AMol. Cell 10:995-1005LEFT-TO-RIGHTTP63/TP53 stimulates transcription of DDIT4 geneTranscription of DDIT4 (REDD1) gene is stimulated by TP63, both during mouse embryonal development and under conditions of genotoxic and oxidative stress. TP53 stimulates DDIT4 transcription after TP53 activation by ionizing radiation, but it seems that TP63 is the main activator of DDIT4 transcription under stress conditions (Ellisen et al. 2002).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23DDIT4DNA damage-inducible transcript 4 proteinREDD1HIF-1 responsive protein RTP801RTP801Reactome DB_ID: 5632374UniProt:Q9NX09 DDIT4DDIT4REDD1RTP801FUNCTION Regulates cell growth, proliferation and survival via inhibition of the activity of the mammalian target of rapamycin complex 1 (mTORC1). Inhibition of mTORC1 is mediated by a pathway that involves DDIT4/REDD1, AKT1, the TSC1-TSC2 complex and the GTPase RHEB. Plays an important role in responses to cellular energy levels and cellular stress, including responses to hypoxia and DNA damage. Regulates p53/TP53-mediated apoptosis in response to DNA damage via its effect on mTORC1 activity. Its role in the response to hypoxia depends on the cell type; it mediates mTORC1 inhibition in fibroblasts and thymocytes, but not in hepatocytes (By similarity). Required for mTORC1-mediated defense against viral protein synthesis and virus replication (By similarity). Inhibits neuronal differentiation and neurite outgrowth mediated by NGF via its effect on mTORC1 activity. Required for normal neuron migration during embryonic brain development. Plays a role in neuronal cell death.SUBUNIT Monomer. Interacts with BTRC. Identified in a complex with CUL4A, DDB1 and BTRC. Interacts with TXNIP; this inhibits the proteasomal degradation of DDIT4.TISSUE SPECIFICITY Broadly expressed, with lowest levels in brain, skeletal muscle and intestine. Up-regulated in substantia nigra neurons from Parkinson disease patients (at protein level).INDUCTION Up-regulated in fibroblasts upon ionizing radiation, via a TP53-dependent pathway. Up-regulated by TP63 in primary keratinocytes, and down-regulated during keratinocyte differentiation. Up-regulated upon DNA alkylation. Up-regulated by amyloid beta-peptide and retinoic acid. Up-regulated by hypoxia, via a PI3K and HIF1A-dependent but TP53/TP63-independent mechanism (at protein level).PTM Phosphorylated by GSK3B; this promotes proteasomal degradation.PTM Polyubiquitinated by a DCX (DDB1-CUL4A-RBX1) E3 ubiquitin-protein ligase complex with BTRC as substrate-recognition component, leading to its proteasomal degradation.SIMILARITY Belongs to the DDIT4 family.UniProtQ9NX091EQUAL232EQUALReactome Database ID Release 755632374Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632374ReactomeR-HSA-56323741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632374.1Reactome Database ID Release 755632386Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632386ReactomeR-HSA-56323864Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632386.4ACTIVATIONactiveUnit: #Complex43Reactome Database ID Release 755632389Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632389ReactomeR-HSA-56323891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632389.1LEFT-TO-RIGHTFormation of TSC1:TSC2 complexA membrane-associated TSC1 (hamartin) binds TSC2 (tuberin) and recruits it to the plasma membrane where it can exert its function as a GAP (GTPase activating protein) for the small GTPase RHEB (Cai et al. 2006). Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23Reactome Database ID Release 75165179Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=165179ReactomeR-HSA-1651792Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-165179.215589136Pubmed2004Signaling pathways: the benefits of good communicationFisher, TLWhite, MFCurr Biol 14:R1005-716636147Pubmed2006Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioningCai, Sheng-LiTee, Andrew RShort, John DBergeron, Judith MKim, JinheeShen, JianjunGuo, RuifengJohnson, Charles LKiguchi, KaoruWalker, Cheryl LynJ. Cell Biol. 173:279-89LEFT-TO-RIGHT2.7.11AKT phosphorylates TSC2, inhibiting itAKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a protein complex with TSC1 and this complex acts as a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.<br>The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.Authored: Nasi, Sergio, Annibali, D, 2006-10-10Reviewed: Greene, LA, 2007-11-08 15:39:37Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-232Phospho-TSC2p-S939,T1462-TSC2Reactome DB_ID: 199484939EQUAL1462EQUAL1EQUAL1807EQUALReactome Database ID Release 75199484Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199484ReactomeR-HSA-1994841Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-199484.12ACTIVATIONactiveUnit: #Protein61Converted from EntitySet in ReactomeActive AKTp-T,p-S-AKTReactome DB_ID: 202074PKBp-T308,S473-AKT1p-S473,T308-AKT1p-T308, S473-AKT1RAC-alpha serine/threonine kinase RAC-PK-alphaProtein kinase BC-AKTReactome DB_ID: 198356UniProt:P31749 AKT1AKT1PKBRACFUNCTION AKT1 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported (PubMed:15526160, PubMed:11882383, PubMed:21620960, PubMed:21432781). AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface (By similarity). Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling (By similarity). Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport (PubMed:11994271). AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity (By similarity). Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven (By similarity). AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase) (PubMed:11154276). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis (PubMed:11154276). AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1 (PubMed:12150915). AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization (PubMed:10358075). In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319' (PubMed:10358075). FOXO3 and FOXO4 are phosphorylated on equivalent sites (PubMed:10358075). AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein) (PubMed:9829964). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1 (PubMed:9829964). AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis (By similarity). Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis (By similarity). Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity (By similarity). The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation (By similarity). Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I) (PubMed:12176338, PubMed:12964941). AKT mediates the antiapoptotic effects of IGF-I (By similarity). Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly (PubMed:19934221). May be involved in the regulation of the placental development (By similarity). Phosphorylates STK4/MST1 at 'Thr-120' and 'Thr-387' leading to inhibition of its: kinase activity, nuclear translocation, autophosphorylation and ability to phosphorylate FOXO3 (PubMed:17726016). Phosphorylates STK3/MST2 at 'Thr-117' and 'Thr-384' leading to inhibition of its: cleavage, kinase activity, autophosphorylation at Thr-180, binding to RASSF1 and nuclear translocation (PubMed:20086174, PubMed:20231902). Phosphorylates SRPK2 and enhances its kinase activity towards SRSF2 and ACIN1 and promotes its nuclear translocation (PubMed:19592491). Phosphorylates RAF1 at 'Ser-259' and negatively regulates its activity (PubMed:10576742). Phosphorylation of BAD stimulates its pro-apoptotic activity (PubMed:10926925). Phosphorylates KAT6A at 'Thr-369' and this phosphorylation inhibits the interaction of KAT6A with PML and negatively regulates its acetylation activity towards p53/TP53 (PubMed:23431171). Phosphorylates palladin (PALLD), modulating cytoskeletal organization and cell motility (PubMed:20471940). Phosphorylates prohibitin (PHB), playing an important role in cell metabolism and proliferation (PubMed:18507042). Phosphorylates CDKN1A, for which phosphorylation at 'Thr-145' induces its release from CDK2 and cytoplasmic relocalization (PubMed:16982699). These recent findings indicate that the AKT1 isoform has a more specific role in cell motility and proliferation (PubMed:16139227). Phosphorylates CLK2 thereby controlling cell survival to ionizing radiation (PubMed:20682768). Phosphorylates PCK1 at 'Ser-90', reducing the binding affinity of PCK1 to oxaloacetate and changing PCK1 into an atypical protein kinase activity using GTP as donor (PubMed:32322062).ACTIVITY REGULATION Three specific sites, one in the kinase domain (Thr-308) and the two other ones in the C-terminal regulatory region (Ser-473 and Tyr-474), need to be phosphorylated for its full activation. Inhibited by pyrrolopyrimidine inhibitors like aniline triazole and spiroindoline.SUBUNIT Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via the C-terminus) with CCDC88A (via its C-terminus). Interacts with GRB10; the interaction leads to GRB10 phosphorylation thus promoting YWHAE-binding (By similarity). Interacts with AGAP2 (isoform 2/PIKE-A); the interaction occurs in the presence of guanine nucleotides. Interacts with AKTIP. Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CDKN1B; the interaction phosphorylates CDKN1B promoting 14-3-3 binding and cell-cycle progression. Interacts with MAP3K5 and TRAF6. Interacts with BAD, PPP2R5B, STK3 and STK4. Interacts (via PH domain) with SIRT1. Interacts with SRPK2 in a phosphorylation-dependent manner. Interacts with RAF1. Interacts with TRIM13; the interaction ubiquitinates AKT1 leading to its proteasomal degradation. Interacts with TNK2 and CLK2. Interacts (via the C-terminus) with THEM4 (via its C-terminus). Interacts with and phosphorylated by PDPK1. Interacts with PA2G4 (By similarity). Interacts with KIF14; the interaction is detected in the plasma membrane upon INS stimulation and promotes AKT1 phosphorylation (PubMed:24784001). Interacts with FAM83B; activates the PI3K/AKT signaling cascade (PubMed:23676467). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529). Forms a complex with WDFY2 and FOXO1 (By similarity). Interacts with FAM168A (PubMed:23251525). Interacts with SYAP1 (via phosphorylated form and BSD domain); this interaction is enhanced in a mTORC2-mediated manner in response to epidermal growth factor (EGF) stimulation and activates AKT1 (PubMed:23300339). Interacts with PKHM3 (By similarity). Interacts with FKBP5/FKBP51; promoting interaction between Akt/AKT1 and PHLPP1, thereby enhancing dephosphorylation and subsequent activation of Akt/AKT1 (PubMed:28147277).TISSUE SPECIFICITY Expressed in prostate cancer and levels increase from the normal to the malignant state (at protein level). Expressed in all human cell types so far analyzed. The Tyr-176 phosphorylated form shows a significant increase in expression in breast cancers during the progressive stages i.e. normal to hyperplasia (ADH), ductal carcinoma in situ (DCIS), invasive ductal carcinoma (IDC) and lymph node metastatic (LNMM) stages.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane. The PH domain mediates interaction with TNK2 and Tyr-176 is also essential for this interaction.DOMAIN The AGC-kinase C-terminal mediates interaction with THEM4.PTM O-GlcNAcylation at Thr-305 and Thr-312 inhibits activating phosphorylation at Thr-308 via disrupting the interaction between AKT1 and PDPK1. O-GlcNAcylation at Ser-473 also probably interferes with phosphorylation at this site.PTM Phosphorylation on Thr-308, Ser-473 and Tyr-474 is required for full activity (PubMed:12149249, PubMed:14761976, PubMed:15047712, PubMed:16266983, PubMed:17013611, PubMed:20978158, PubMed:9736715, PubMed:23799035, PubMed:8978681, PubMed:28147277). Activated TNK2 phosphorylates it on Tyr-176 resulting in its binding to the anionic plasma membrane phospholipid PA (PubMed:20333297). This phosphorylated form localizes to the cell membrane, where it is targeted by PDPK1 and PDPK2 for further phosphorylations on Thr-308 and Ser-473 leading to its activation (PubMed:9512493). Ser-473 phosphorylation by mTORC2 favors Thr-308 phosphorylation by PDPK1 (PubMed:21464307, PubMed:8978681). Phosphorylated at Thr-308 and Ser-473 by IKBKE and TBK1 (PubMed:15718470, PubMed:18456494, PubMed:20481595, PubMed:8978681). Ser-473 phosphorylation is enhanced by interaction with AGAP2 isoform 2 (PIKE-A) (PubMed:14761976). Ser-473 phosphorylation is enhanced in focal cortical dysplasias with Taylor-type balloon cells (PubMed:17013611). Ser-473 phosphorylation is enhanced by signaling through activated FLT3 (By similarity). Ser-473 is dephosphorylated by PHLPP (PubMed:28147277). Dephosphorylated at Thr-308 and Ser-473 by PP2A phosphatase (PubMed:21329884). The phosphorylated form of PPP2R5B is required for bridging AKT1 with PP2A phosphatase (PubMed:21329884). Ser-473 is dephosphorylated by CPPED1, leading to termination of signaling (PubMed:9512493).PTM Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity). Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation. When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome. Also ubiquitinated by TRIM13 leading to its proteasomal degradation. Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation.PTM Acetylated on Lys-14 and Lys-20 by the histone acetyltransferases EP300 and KAT2B. Acetylation results in reduced phosphorylation and inhibition of activity. Deacetylated at Lys-14 and Lys-20 by SIRT1. SIRT1-mediated deacetylation relieves the inhibition.DISEASE Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.UniProtP31749308EQUAL473EQUAL1EQUAL480EQUALReactome Database ID Release 75198356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198356ReactomeR-HSA-1983561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198356.1PKB betap-T309,S474-AKT2p-S474,T309-AKT2p-T309, S474-AKT2RAC-beta serine/threonine protein kinase RAC-PK-betaProtein kinase Akt-2Protein kinase B, betaReactome DB_ID: 202062UniProt:P31751 AKT2AKT2FUNCTION AKT2 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT is responsible of the regulation of glucose uptake by mediating insulin-induced translocation of the SLC2A4/GLUT4 glucose transporter to the cell surface. Phosphorylation of PTPN1 at 'Ser-50' negatively modulates its phosphatase activity preventing dephosphorylation of the insulin receptor and the attenuation of insulin signaling. Phosphorylation of TBC1D4 triggers the binding of this effector to inhibitory 14-3-3 proteins, which is required for insulin-stimulated glucose transport. AKT regulates also the storage of glucose in the form of glycogen by phosphorylating GSK3A at 'Ser-21' and GSK3B at 'Ser-9', resulting in inhibition of its kinase activity. Phosphorylation of GSK3 isoforms by AKT is also thought to be one mechanism by which cell proliferation is driven. AKT regulates also cell survival via the phosphorylation of MAP3K5 (apoptosis signal-related kinase). Phosphorylation of 'Ser-83' decreases MAP3K5 kinase activity stimulated by oxidative stress and thereby prevents apoptosis. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 at 'Ser-939' and 'Thr-1462', thereby activating mTORC1 signaling and leading to both phosphorylation of 4E-BP1 and in activation of RPS6KB1. AKT is involved in the phosphorylation of members of the FOXO factors (Forkhead family of transcription factors), leading to binding of 14-3-3 proteins and cytoplasmic localization. In particular, FOXO1 is phosphorylated at 'Thr-24', 'Ser-256' and 'Ser-319'. FOXO3 and FOXO4 are phosphorylated on equivalent sites. AKT has an important role in the regulation of NF-kappa-B-dependent gene transcription and positively regulates the activity of CREB1 (cyclic AMP (cAMP)-response element binding protein). The phosphorylation of CREB1 induces the binding of accessory proteins that are necessary for the transcription of pro-survival genes such as BCL2 and MCL1. AKT phosphorylates 'Ser-454' on ATP citrate lyase (ACLY), thereby potentially regulating ACLY activity and fatty acid synthesis. Activates the 3B isoform of cyclic nucleotide phosphodiesterase (PDE3B) via phosphorylation of 'Ser-273', resulting in reduced cyclic AMP levels and inhibition of lipolysis. Phosphorylates PIKFYVE on 'Ser-318', which results in increased PI(3)P-5 activity. The Rho GTPase-activating protein DLC1 is another substrate and its phosphorylation is implicated in the regulation cell proliferation and cell growth. AKT plays a role as key modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including correct neuron positioning, dendritic development and synapse formation. Signals downstream of phosphatidylinositol 3-kinase (PI(3)K) to mediate the effects of various growth factors such as platelet-derived growth factor (PDGF), epidermal growth factor (EGF), insulin and insulin-like growth factor I (IGF-I). AKT mediates the antiapoptotic effects of IGF-I. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. May be involved in the regulation of the placental development.FUNCTION One of the few specific substrates of AKT2 identified recently is PITX2. Phosphorylation of PITX2 impairs its association with the CCND1 mRNA-stabilizing complex thus shortening the half-life of CCND1. AKT2 seems also to be the principal isoform responsible of the regulation of glucose uptake. Phosphorylates C2CD5 on 'Ser-197' during insulin-stimulated adipocytes. AKT2 is also specifically involved in skeletal muscle differentiation, one of its substrates in this process being ANKRD2. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis. Phosphorylates CLK2 on 'Thr-343'.ACTIVITY REGULATION Two specific sites, one in the kinase domain (Thr-309) and the other in the C-terminal regulatory region (Ser-474), need to be phosphorylated for its full activation. Aminofurazans are potent AKT2 inhibitors.SUBUNIT Interacts with BTBD10 (By similarity). Interacts with KCTD20 (By similarity). Interacts (via PH domain) with MTCP1, TCL1A AND TCL1B. Interacts with CLK2, PBH2 and TRAF6. Interacts (when phosphorylated) with CLIP3, the interaction promotes cell membrane localization (PubMed:19139280). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529).TISSUE SPECIFICITY Expressed in all cell types so far analyzed.DOMAIN Binding of the PH domain to phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) following phosphatidylinositol 3-kinase alpha (PIK3CA) activity results in its targeting to the plasma membrane.PTM Phosphorylation on Thr-309 and Ser-474 is required for full activity.PTM Ubiquitinated; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT2 ubiquitination. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.PTM O-GlcNAcylation at Thr-306 and Thr-313 inhibits activating phosphorylation at Thr-309 via disrupting the interaction between AKT and PDK1.DISEASE Defects in AKT2 are a cause of susceptibility to breast cancer (BC). AKT2 promotes metastasis of tumor cells without affecting the latency of tumor development. With AKT3, plays also a pivotal role in the biology of glioblastoma.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.UniProtP31751309EQUAL474EQUAL1EQUAL481EQUALReactome Database ID Release 75202062Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202062ReactomeR-HSA-2020621Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202062.1AKT3p-T305,S472-AKT3RAC-gamma serine/threonine-protein kinase ecNumber2.7.11.1/ecNumberAKT3_HUMANReactome DB_ID: 3009367UniProt:Q9Y243 AKT3AKT3PKBGFUNCTION AKT3 is one of 3 closely related serine/threonine-protein kinases (AKT1, AKT2 and AKT3) called the AKT kinase, and which regulate many processes including metabolism, proliferation, cell survival, growth and angiogenesis. This is mediated through serine and/or threonine phosphorylation of a range of downstream substrates. Over 100 substrate candidates have been reported so far, but for most of them, no isoform specificity has been reported. AKT3 is the least studied AKT isoform. It plays an important role in brain development and is crucial for the viability of malignant glioma cells. AKT3 isoform may also be the key molecule in up-regulation and down-regulation of MMP13 via IL13. Required for the coordination of mitochondrial biogenesis with growth factor-induced increases in cellular energy demands. Down-regulation by RNA interference reduces the expression of the phosphorylated form of BAD, resulting in the induction of caspase-dependent apoptosis.ACTIVITY REGULATION Two specific sites, one in the kinase domain (Thr-305) and the other in the C-terminal regulatory region (Ser-472), need to be phosphorylated for its full activation (By similarity). IGF-1 leads to the activation of AKT3, which may play a role in regulating cell survival.SUBUNIT Interacts (via PH domain) with TCL1A; this enhances AKT3 phosphorylation and activation. Interacts with TRAF6. Interacts with KCTD20 (By similarity). Interacts with BTBD10 (By similarity).TISSUE SPECIFICITY In adult tissues, it is highly expressed in brain, lung and kidney, but weakly in heart, testis and liver. In fetal tissues, it is highly expressed in heart, liver and brain and not at all in kidney.DOMAIN Binding of the PH domain to the phosphatidylinositol 3-kinase alpha (PI(3)K) results in its targeting to the plasma membrane.PTM Phosphorylation on Thr-305 and Ser-472 is required for full activity.PTM Ubiquitinated. When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome.PTM O-GlcNAcylation at Thr-302 and Thr-309 inhibits activating phosphorylation at Thr-305 via disrupting the interaction between AKT and PDK1.DISEASE AKT3 is a key modulator of several tumors like melanoma, glioma and ovarian cancer. Active AKT3 increases progressively during melanoma tumor progression with highest levels present in advanced-stage metastatic melanomas. Promotes melanoma tumorigenesis by decreasing apoptosis. Plays a key role in the genesis of ovarian cancers through modulation of G2/M phase transition. With AKT2, plays a pivotal role in the biology of glioblastoma.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION In light of strong homologies in the primary amino acid sequence, the 3 AKT kinases were long surmised to play redundant and overlapping roles. More recent studies has brought into question the redundancy within AKT kinase isoforms and instead pointed to isoform specific functions in different cellular events and diseases. AKT1 is more specifically involved in cellular survival pathways, by inhibiting apoptotic processes; whereas AKT2 is more specific for the insulin receptor signaling pathway. Moreover, while AKT1 and AKT2 are often implicated in many aspects of cellular transformation, the 2 isoforms act in a complementary opposing manner. The role of AKT3 is less clear, though it appears to be predominantly expressed in brain.UniProtQ9Y243305EQUAL472EQUAL1EQUAL479EQUALReactome Database ID Release 753009367Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3009367ReactomeR-HSA-30093671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3009367.1Reactome Database ID Release 75202074Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202074ReactomeR-HSA-2020742Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-202074.2GENE ONTOLOGYGO:0004674Reactome Database ID Release 75198368Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198368Reactome Database ID Release 75198609Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198609ReactomeR-HSA-1986095Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-198609.512150915Pubmed2002Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathwayManning, BDTee, ARLogsdon, MNBlenis, JCantley, Lewis CMol Cell 10:151-6212172553Pubmed2002TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signallingInoki, KLi, YunZhu, TWu, JGuan, KLNat Cell Biol 4:648-57GENE ONTOLOGYGO:0043491gene ontology term for cellular processMIMI:0359LEFT-TO-RIGHTp-S939,T1462-TSC2 binding to 14-3-3 dimer is negatively regulated by DDIT4Phosphorylation of TSC2 by AKT enables association of TSC2 with 14-3-3 proteins YWHAB (14-3-3 protein beta/alpha), YWHAQ (14-3-3 protein theta), YWHAG (14-3-3 protein gamma), YWHAH (14-3-3 protein eta), YWHAE (14-3-3 protein epsilon), YWHAZ (14-3-3 protein zeta/delta) or SFN (14-3-3 protein sigma) (Liu et al. 2002). Binding to 14-3-3 proteins sequesters TSC2 to the cytosol and prevents its association with TSC1 (Cai et al. 2006).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23Converted from EntitySet in Reactome14-3-3 dimerReactome DB_ID: 144513814-3-3 eta dimerReactome DB_ID: 2262715YWHAH14-3-3 eta14-3-3 protein eta1433F_HUMANReactome DB_ID: 1445107UniProt:Q04917 YWHAHYWHAHYWHA1FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1.SUBUNIT Homodimer (By similarity). Interacts with many nuclear hormone receptors and cofactors including AR, ESR1, ESR2, MC2R, NR3C1, NRIP1, PPARBP and THRA. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with ARHGEF28 and CDK16 (By similarity). Weakly interacts with CDKN1B. Interacts with GAB2. Interacts with KCNK18 in a phosphorylation-dependent manner. Interacts with SAMSN1 (By similarity). Interacts with the 'Ser-241' phosphorylated form of PDPK1. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509).TISSUE SPECIFICITY Expressed mainly in the brain and present in other tissues albeit at lower levels.PTM Phosphorylated on Ser-59 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.SIMILARITY Belongs to the 14-3-3 family.UniProtQ049172EQUAL246EQUALReactome Database ID Release 751445107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445107ReactomeR-HSA-14451071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445107.12Reactome Database ID Release 752262715Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262715ReactomeR-HSA-22627151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262715.1YWHAG dimer14-3-3 gamma dimerReactome DB_ID: 2262713YWHAG14-3-3 protein gamma14-3-3 gammaReactome DB_ID: 380312UniProt:P61981 YWHAGYWHAGFUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner.SUBUNIT Homodimer. Interacts with SAMSN1 (By similarity). Interacts with RAF1, SSH1 and CRTC2/TORC2. Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm. Interacts with GAB2. Interacts with MDM4 (phosphorylated); negatively regulates MDM4 activity toward TP53. Interacts with PKA-phosphorylated AANAT and SIRT2.Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with LRRK2; this interaction is dependent on LRRK2 phosphorylation (PubMed:28202711). Interacts with MARK2 and MARK3 (PubMed:16959763).TISSUE SPECIFICITY Highly expressed in brain, skeletal muscle, and heart.PTM Phosphorylated by various PKC isozymes.SIMILARITY Belongs to the 14-3-3 family.UniProtP619811EQUAL247EQUALReactome Database ID Release 75380312Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=380312ReactomeR-HSA-3803121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-380312.12Reactome Database ID Release 752262713Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262713ReactomeR-HSA-22627132Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262713.2SFN dimer14-3-3 sigma dimerReactome DB_ID: 2262716SFN14-3-3 sigma14-3-3 protein sigma1433S_HUMANReactome DB_ID: 1445105UniProt:P31947 SFNSFNHME1FUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. When bound to KRT17, regulates protein synthesis and epithelial cell growth by stimulating Akt/mTOR pathway. May also regulate MDM2 autoubiquitination and degradation and thereby activate p53/TP53.FUNCTION p53-regulated inhibitor of G2/M progression.SUBUNIT Homodimer (PubMed:28202711). Interacts with KRT17 and SAMSN1 (By similarity). Found in a complex with XPO7, EIF4A1, ARHGAP1, VPS26A, VPS29 and VPS35. Interacts with GAB2. Interacts with SRPK2. Interacts with COPS6. Interacts with COP1; this interaction leads to proteasomal degradation. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with LRRK2; this interaction is dependent on LRRK2 phosphorylation (PubMed:28202711).TISSUE SPECIFICITY Present mainly in tissues enriched in stratified squamous keratinizing epithelium.PTM Ubiquitinated. Ubiquitination by RFFL induces proteasomal degradation and indirectly regulates p53/TP53 activation.SIMILARITY Belongs to the 14-3-3 family.UniProtP319471EQUAL248EQUALReactome Database ID Release 751445105Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445105ReactomeR-HSA-14451051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445105.12Reactome Database ID Release 752262716Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262716ReactomeR-HSA-22627163Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262716.3YWHAQ dimer14-3-3 theta dimerReactome DB_ID: 2262714YWHAQ14-3-3 theta14-3-3 protein theta1433T_HUMANReactome DB_ID: 1445116UniProt:P27348 YWHAQYWHAQFUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negatively regulates the kinase activity of PDPK1.SUBUNIT Homodimer. Interacts with CDK16 (By similarity). Interacts with RGS7 (phosphorylated form) (PubMed:10862767). Interacts with SSH1. Interacts with CDKN1B ('Thr-198' phosphorylated form); the interaction translocates CDKN1B to the cytoplasm. Interacts with GAB2. Interacts with the 'Ser-241' phosphorylated form of PDPK1. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with SLITRK1 (PubMed:19640509). Interacts with RIPOR2 isoform 2 (PubMed:25588844). Interacts with INAVA; the interaction increases upon PRR (pattern recognition receptor) stimulation and is required for cellular signaling pathway activation and cytokine secretion (PubMed:28436939). Interacts with MARK2, MARK3 and MARK4 (PubMed:16959763).TISSUE SPECIFICITY Abundantly expressed in brain, heart and pancreas, and at lower levels in kidney and placenta. Up-regulated in the lumbar spinal cord from patients with sporadic amyotrophic lateral sclerosis (ALS) compared with controls, with highest levels of expression in individuals with predominant lower motor neuron involvement.PTM Ser-232 is probably phosphorylated by CK1.SIMILARITY Belongs to the 14-3-3 family.UniProtP273481EQUAL245EQUALReactome Database ID Release 751445116Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445116ReactomeR-HSA-14451161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445116.12Reactome Database ID Release 752262714Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2262714ReactomeR-HSA-22627142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2262714.2YWHAZ dimer14-3-3 zeta dimerReactome DB_ID: 206751YWHAZ14-3-3 zetaReactome DB_ID: 206099UniProt:P63104 YWHAZYWHAZFUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Induces ARHGEF7 activity on RAC1 as well as lamellipodia and membrane ruffle formation (PubMed:16959763). In neurons, regulates spine maturation through the modulation of ARHGEF7 activity (By similarity).SUBUNIT Interacts with CDK16 and BSPRY (By similarity). Interacts with WEE1 (C-terminal). Interacts with SAMSN1 (By similarity). Interacts with MLF1 (phosphorylated form); the interaction retains it in the cytoplasm (By similarity). Interacts with Thr-phosphorylated ITGB2 (By similarity). Interacts with BCL2L11 (By similarity). Homodimer. Heterodimerizes with YWHAE. Homo- and heterodimerization is inhibited by phosphorylation on Ser-58. Interacts with FOXO4, NOXA1, SSH1 and ARHGEF2. Interacts with Pseudomonas aeruginosa exoS (unphosphorylated form). Interacts with BAX; the interaction occurs in the cytoplasm. Under stress conditions, MAPK8-mediated phosphorylation releases BAX to mitochondria. Interacts with phosphorylated RAF1; the interaction is inhibited when YWHAZ is phosphorylated on Thr-232 (PubMed:31024343). Interacts with BRAF (PubMed:31024343). Interacts with TP53; the interaction enhances p53 transcriptional activity. The Ser-58 phosphorylated form inhibits this interaction and p53 transcriptional activity. Interacts with ABL1 (phosphorylated form); the interaction retains ABL1 in the cytoplasm. Interacts with PKA-phosphorylated AANAT; the interaction modulates AANAT enzymatic activity by increasing affinity for arylalkylamines and acetyl-CoA and protecting the enzyme from dephosphorylation and proteasomal degradation. It may also prevent thiol-dependent inactivation. Interacts with AKT1; the interaction phosphorylates YWHAZ and modulates dimerization. Interacts with GAB2 and TLK2. Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with ZFP36L1 (via phosphorylated form); this interaction occurs in a p38 MAPK- and AKT-signaling pathways (By similarity). Interacts with SLITRK1 (PubMed:19640509). Interacts with AK5, LDB1, MADD, MARK3, PDE1A and SMARCB1 (PubMed:16959763).PTM The delta, brain-specific form differs from the zeta form in being phosphorylated (By similarity). Phosphorylation on Ser-184 by MAPK8; promotes dissociation of BAX and translocation of BAX to mitochondria. Phosphorylation on Thr-232; inhibits binding of RAF1. Phosphorylated on Ser-58 by PKA and protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion. Phosphorylation on Ser-58 by PKA; disrupts homodimerization and heterodimerization with YHAE and TP53.SIMILARITY Belongs to the 14-3-3 family.CAUTION Was originally thought to have phospholipase A2 activity.UniProtP631041EQUAL245EQUALReactome Database ID Release 75206099Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=206099ReactomeR-HSA-2060991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-206099.12Reactome Database ID Release 75206751Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=206751ReactomeR-HSA-2067513Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-206751.3YWHAB dimerReactome DB_ID: 2028645YWHAB14-3-3 protein beta/alpha143B proteinProtein kinase C inhibitor protein-1KCIP-1Protein 1054Reactome DB_ID: 48888UniProt:P31946 YWHABYWHABFUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2. Negative regulator of signaling cascades that mediate activation of MAP kinases via AKAP13.SUBUNIT Homodimer (PubMed:17717073). Interacts with SAMSN1 and PRKCE (By similarity). Interacts with AKAP13 (PubMed:21224381). Interacts with SSH1 and TORC2/CRTC2 (PubMed:15454081, PubMed:15159416). Interacts with ABL1; the interaction results in cytoplasmic location of ABL1 and inhibition of cABL-mediated apoptosis (PubMed:15696159). Interacts with ROR2 (dimer); the interaction results in phosphorylation of YWHAB on tyrosine residues (PubMed:17717073). Interacts with GAB2 (PubMed:19172738). Interacts with YAP1 (phosphorylated form) (PubMed:17974916). Interacts with the phosphorylated (by AKT1) form of SRPK2 (PubMed:19592491). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with MYO1C (PubMed:24636949). Interacts with SIRT2 (PubMed:18249187). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (PubMed:22827337). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1-dependent manner (PubMed:15538381). Interacts with SLITRK1 (PubMed:19640509). Interacts with SYNPO2 (phosphorylated form); YWHAB competes with ACTN2 for interaction with SYNPO2 (By similarity). Interacts with RIPOR2 (via phosphorylated form) isoform 2; this interaction occurs in a chemokine-dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2-mediated RHOA activity (PubMed:25588844). Interacts with MARK2 and MARK3 (PubMed:16959763).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL46.SUBUNIT (Microbial infection) Probably interacts with Chlamydia trachomatis protein IncG.PTM The alpha, brain-specific form differs from the beta form in being phosphorylated. Phosphorylated on Ser-60 by protein kinase C delta type catalytic subunit in a sphingosine-dependent fashion.SIMILARITY Belongs to the 14-3-3 family.UniProtP319461EQUAL246EQUALReactome Database ID Release 7548888Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=48888ReactomeR-HSA-488881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-48888.12Reactome Database ID Release 752028645Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2028645ReactomeR-HSA-20286451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2028645.1YWHAE dimer14-3-3E homodimerReactome DB_ID: 194364YWHAE14-3-3 protein epsilon143E_HUMAN14-3-3 epsilonReactome DB_ID: 194368UniProt:P62258 YWHAEYWHAEFUNCTION Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner (By similarity). Positively regulates phosphorylated protein HSF1 nuclear export to the cytoplasm (PubMed:12917326).SUBUNIT Homodimer (PubMed:17085597). Heterodimerizes with YWHAZ (PubMed:16376338). Interacts with PKA-phosphorylated AANAT (PubMed:11427721). Interacts with ABL1 (phosphorylated form); the interaction retains it in the cytoplasm (PubMed:15696159). Interacts with ARHGEF28 (By similarity). Interacts with BEX3 (By similarity). Weakly interacts with CDKN1B (PubMed:12042314). Interacts with the 'Thr-369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with DENND1A (PubMed:26055712). Interacts with GAB2 (PubMed:19172738). Interacts with phosphorylated GRB10 (PubMed:15722337). Interacts with KSR1 (PubMed:10409742). Interacts with NDEL1 (By similarity). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with the phosphorylated (by AKT1) form of SRPK2 (PubMed:19592491). Interacts with TIAM2. Interacts with the 'Ser-1134' and 'Ser-1161' phosphorylated form of SOS1 (By similarity). Interacts with ZFP36 (via phosphorylated form) (By similarity). Interacts with SLITRK1 (PubMed:19640509). Interacts with HSF1 (via phosphorylated form); this interaction promotes HSF1 sequestration in the cytoplasm in a ERK-dependent manner (PubMed:12917326). Interacts with RIPOR2 isoform 2 (PubMed:25588844). Interacts with KLHL22; required for the nuclear localization of KLHL22 upon amino acid starvation (PubMed:29769719). Interacts with CRTC1 (PubMed:30611118). Interacts with CRTC2 (probably when phosphorylated at 'Ser-171') (PubMed:30611118). Interacts with CRTC3 (probably when phosphorylated at 'Ser-162' and/or 'Ser-273') (PubMed:30611118). Interacts with ATP2B1; this interaction inhibits calcium-transporting ATPase activity (PubMed:18029012).SUBUNIT (Microbial infection) Interacts with HCV core protein.SIMILARITY Belongs to the 14-3-3 family.UniProtP622581EQUAL255EQUALReactome Database ID Release 75194368Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194368ReactomeR-HSA-1943681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194368.12Reactome Database ID Release 75194364Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=194364ReactomeR-HSA-1943641Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-194364.1Reactome Database ID Release 751445138Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1445138ReactomeR-HSA-14451381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1445138.1p-S939,T1462-TSC2:14-3-3 dimerReactome DB_ID: 563272711Reactome Database ID Release 755632727Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632727ReactomeR-HSA-56327271Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632727.1Reactome Database ID Release 755632732Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632732ReactomeR-HSA-56327324Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632732.412438239Pubmed200214-3-3 interacts with the tumor suppressor tuberin at Akt phosphorylation site(s)Liu, Matt YCai, ShengliEspejo, AlexsandraBedford, Mark TWalker, Cheryl LynCancer Res. 62:6475-80INHIBITIONactiveUnit: #Protein59Reactome Database ID Release 755632745Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632745ReactomeR-HSA-56327452Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632745.2DDIT4:14-3-3 dimerReactome DB_ID: 563274111Reactome Database ID Release 755632741Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632741ReactomeR-HSA-56327411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632741.1LEFT-TO-RIGHTDDIT4 binds 14-3-3 dimerDDIT4 (REDD1) binds 14-3-3 proteins through a conserved 14-3-3 binding motif Arg-X-X-X-Ser/Thr-X-Pro (DeYoung et al. 2008). Binding of DDIT4 to 14-3-3 proteins competes with 14-3-3 binding to TSC2 and thus prevents AKT-mediated inactivation of TSC2 (Cam et al. 2014).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23Reactome Database ID Release 755632738Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632738ReactomeR-HSA-56327382Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632738.218198340Pubmed2008Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttlingDeYoung, Maurice PhillipHorak, PeterSofer, AviSgroi, DennisEllisen, Leif WGenes Dev. 22:239-51LEFT-TO-RIGHTTP53 binds the SCO2 geneTP53 (p53) binds the p53 response element in the intron 1 of SCO2 (Synthesis of Cytochrome c Oxidase 2) gene (Matoba et al. 2006). The binding of TP53 on SCO2 gene was verified in a genome wide chromatin immunoprecipitation study (Wei et al. 2006). Tp53 was also found to bind to the promoter region in mouse Sco2 gene to stimulate its expression in response to physical exercise (Qi et al. 2011).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23SCO2 GeneReactome DB_ID: 5632758ENSEMBL:ENSG00000130489 SCO2SCO2ENSEMBLENSG00000130489Reactome Database ID Release 755632758Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632758ReactomeR-HSA-56327581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632758.1TP53 Tetramer:SCO2 GeneReactome DB_ID: 563275511Reactome Database ID Release 755632755Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632755ReactomeR-HSA-56327551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632755.1Reactome Database ID Release 755632759Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632759ReactomeR-HSA-56327594Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632759.416728594Pubmed2006p53 regulates mitochondrial respirationMatoba, SatoakiKang, Ju-GyeongPatino, Willmar DWragg, AndrewBoehm, ManfredGavrilova, OksanaHurley, Paula JBunz, FredHwang, Paul MScience 312:1650-316413492Pubmed2006A global map of p53 transcription-factor binding sites in the human genomeWei, Chia-LinWu, QiangVega, Vinsensius BChiu, Kuo PingNg, PatrickZhang, TShahab, AtifYong, How ChoongFu, YuTaoWeng, ZhipingLiu, JianJunZhao, Xiao DongChew, Joon-LinLee, Yen LingKuznetsov, Vladimir ASung, Wing-KinMiller, Lance DLim, BingLiu, Edison TYu, QiangNg, Huck-HuiRuan, YijunCell 124:207-1921750704Pubmed2011Physical exercise regulates p53 activity targeting SCO2 and increases mitochondrial COX biogenesis in cardiac muscle with ageQi, ZhengtangHe, JieSu, YuhuiHe, QiangLiu, JingxiaYu, LuAl-Attas, OmarHussain, TajamulDing, ShuzheJi, LiuQian, MinPLoS ONE 6:e21140LEFT-TO-RIGHTTP53 stimulates SCO2 gene transcriptionTP53 (p53) directly stimulates transcription of the SCO2 gene. SCO2, synthesis of cytochrome c oxidase 2, is a copper-binding assembly protein for the mitochondrial COX (cytochrome C oxidase) complex which enables aerobic respiration. When SCO2 levels are reduced, as occurs in TP53 deficient cells, the glycolysis becomes the main energy source for the cell. The TP53-mediated regulation of SCO2 and other mitochondrial biogenesis genes provides a possible explanation for the Warburg effect (Warburg 1956) observed in some cancer cells (Matoba et al. 2006).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23SCO2Protein SCO2 homolog, mitochondrialSCO2_HUMANReactome DB_ID: 5336150mitochondrial matrixGENE ONTOLOGYGO:0005759UniProt:O43819 SCO2SCO2FUNCTION Copper metallochaperone essential for the synthesis and maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Involved in transporting copper to the Cu(A) site on MT-CO2/COX2 (PubMed:15229189, PubMed:17189203). Also acts as a thiol-disulfide oxidoreductase to regulate the redox state of the cysteines in SCO1 during maturation of MT-CO2/COX2 (PubMed:19336478).SUBUNIT Homodimer (PubMed:15229189). Interacts with COA6 (PubMed:25959673). Found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO1 (PubMed:29154948). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948). Interacts with COX20 in a MT-CO2/COX2- and COX18-dependent manner (PubMed:29154948, PubMed:24403053, PubMed:28330871). Interacts with COX16 (PubMed:29381136).TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the SCO1/2 family.UniProtO4381942EQUAL266EQUALReactome Database ID Release 755336150Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336150ReactomeR-HSA-53361501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336150.1Reactome Database ID Release 755632766Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632766ReactomeR-HSA-56327664Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632766.413298683Pubmed1956On the origin of cancer cellsWARBURG, OScience 123:309-14ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 755632769Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632769ReactomeR-HSA-56327691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632769.1LEFT-TO-RIGHT1.9.3.1Electron transfer from reduced cytochrome c to molecular oxygenComplex IV (COX, cytochrome c oxidase) contains the hemeprotein cytochrome a and a3. It also contains copper atoms which undergo a transition from Cu+ to Cu2+ during the transfer of electrons through the complex to molecular oxygen. A bimetallic centre containing a copper atom and a heme-linked iron protein binds oxygen after 4 electrons have been picked up. Water, the final product of oxygen reduction, is then released. Oxygen is the final electron acceptor in the respiratory chain. The overall reaction can be summed as<br><br>4Cyt c (red.) + 12H+ (in) + O2 = 4Cyt c (ox.) + 2H2O + 8H+ (out)<br><br>Four protons are taken up from the matrix side of the membrane to form the water (scalar protons). Wikstrom (1977) suggests 4 protons are additionally transferred out from the matrix to the intermembrane space.<br><br>COX ancillary proteins mediate membrane insertion, catalytic core processing, copper transport and insertion into core subunits and heme A biosynthesis (Stilburek et al. 2006, Fontanesi et al. 2006, Soto et al. 2012). To date, all Mendelian disorders presenting COX deficiency have been assigned to mutations in ancillary factors, with the exception of an infantile encephalomyopathy caused by a defective COX6B1 and an exocrine pancreatic insufficiency caused by a defective COX4I2 gene (Soto et al. 2012). Balsa et al have shown that NDUFA4, formerly considered to be a constituent of NADH dehydrogenase (Complex I), is instead a component of the cytochrome c oxidase (CIV) (Balsa et al. 2012). Patients with NDUFA4 mutations display COX deficiencies (Pitceathly et al. 2013).Authored: Jassal, Bijay, 2005-06-28Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Jassal, Bijay, 2005-04-25O2OxygendioxygenReactome DB_ID: 113533dioxygen [ChEBI:15379]dioxygenChEBICHEBI:15379Reactome Database ID Release 75113533Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113533ReactomeR-ALL-1135333Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113533.3COMPOUNDC00007Cytochrome c-Fe2+Cytochrome c (reduced)Ferrous cytochrome cReactome DB_ID: 352609mitochondrial inner membraneGENE ONTOLOGYGO:0005743CYCSCytochrome cReactome DB_ID: 352608UniProt:P99999 CYCSCYCSCYCFUNCTION Electron carrier protein. The oxidized form of the cytochrome c heme group can accept an electron from the heme group of the cytochrome c1 subunit of cytochrome reductase. Cytochrome c then transfers this electron to the cytochrome oxidase complex, the final protein carrier in the mitochondrial electron-transport chain.FUNCTION Plays a role in apoptosis. Suppression of the anti-apoptotic members or activation of the pro-apoptotic members of the Bcl-2 family leads to altered mitochondrial membrane permeability resulting in release of cytochrome c into the cytosol. Binding of cytochrome c to Apaf-1 triggers the activation of caspase-9, which then accelerates apoptosis by activating other caspases.PTM Binds 1 heme group per subunit.PTM Phosphorylation at Tyr-49 and Tyr-98 both reduce by half the turnover in the reaction with cytochrome c oxidase, down-regulating mitochondrial respiration.SIMILARITY Belongs to the cytochrome c family.UniProtP999992EQUAL105EQUALReactome Database ID Release 75352608Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=352608ReactomeR-HSA-3526081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-352608.11ferrohemeReactome DB_ID: 3341317ferroheme [ChEBI:38573]ferrohemeferrohaemChEBICHEBI:38573Reactome Database ID Release 753341317Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341317ReactomeR-ALL-33413172Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-3341317.21Reactome Database ID Release 75352609Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=352609ReactomeR-HSA-3526091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-352609.14H+hydronReactome DB_ID: 113529Reactome Database ID Release 75113529Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113529ReactomeR-ALL-1135294Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113529.4COMPOUNDC0008012Cytochrome c-Fe3+Cytochrome c (oxidised)Ferric cytochrome cReactome DB_ID: 3526071ferrihemeReactome DB_ID: 3341371ferriheme [ChEBI:38574]ferrihemeferrihaemChEBICHEBI:38574Reactome Database ID Release 753341371Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3341371ReactomeR-ALL-33413712Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-3341371.21Reactome Database ID Release 75352607Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=352607ReactomeR-HSA-3526071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-352607.14H2OwaterReactome DB_ID: 113521Reactome Database ID Release 75113521Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113521ReactomeR-ALL-1135213Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113521.3COMPOUNDC000012H+hydronReactome DB_ID: 163953mitochondrial intermembrane spaceGENE ONTOLOGYGO:0005758Reactome Database ID Release 75163953Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163953ReactomeR-ALL-1639533Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-163953.3COMPOUNDC000808ACTIVATIONComplex IVCytochrome c oxidaseReactome DB_ID: 164316MT-CO2:CuAComplex IV - Cytochrome c oxidase subunit 2-Cu complexReactome DB_ID: 164303CuACopper Acopper atomReactome DB_ID: 164300copper atom [ChEBI:28694]copper atomCucopper29CucuprumcuivreKupfercobreCopperChEBICHEBI:28694Reactome Database ID Release 75164300Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164300ReactomeR-ALL-1643003Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-164300.3COMPOUNDC000701MT-CO2Cytochrome c oxidase subunit 2Cytochrome c oxidase polypeptide IIReactome DB_ID: 164302UniProt:P00403 MT-CO2MT-CO2COIICOX2COXIIMTCO2FUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Found in a complex with TMEM177, COA6, COX18, COX20, SCO1 and SCO2 (PubMed:29154948). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948). Interacts with COX20 (PubMed:23125284, PubMed:24403053, PubMed:28330871, PubMed:29154948). Interacts with COX16 (PubMed:29355485, PubMed:29381136).SIMILARITY Belongs to the cytochrome c oxidase subunit 2 family.UniProtP004031EQUAL227EQUALReactome Database ID Release 75164302Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164302ReactomeR-HSA-1643021Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164302.11Reactome Database ID Release 75164303Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164303ReactomeR-HSA-1643031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164303.11MT-CO3Cytochrome c oxidase subunit 3Cytochrome c oxidase polypeptide IIIReactome DB_ID: 164312UniProt:P00414 MT-CO3MT-CO3COIIICOXIIIMTCO3FUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).SIMILARITY Belongs to the cytochrome c oxidase subunit 3 family.UniProtP004142EQUAL261EQUALReactome Database ID Release 75164312Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164312ReactomeR-HSA-1643121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164312.11COX6C(3-75)Cytochrome c oxidase polypeptide VIcReactome DB_ID: 164298UniProt:P09669 COX6CCOX6CFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).SIMILARITY Belongs to the cytochrome c oxidase subunit 6c family.UniProtP096693EQUAL75EQUALReactome Database ID Release 75164298Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164298ReactomeR-HSA-1642981Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164298.11COX5BCytochrome c oxidase polypeptide VbReactome DB_ID: 164307UniProt:P10606 COX5BCOX5BFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).SIMILARITY Belongs to the cytochrome c oxidase subunit 5B family.UniProtP1060632EQUAL129EQUALReactome Database ID Release 75164307Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164307ReactomeR-HSA-1643071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164307.11COX6A1Cytochrome c oxidase polypeptide VIaReactome DB_ID: 164301UniProt:P12074 COX6A1COX6A1COX6ALFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules unsing 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).SIMILARITY Belongs to the cytochrome c oxidase subunit 6A family.UniProtP1207425EQUAL109EQUALReactome Database ID Release 75164301Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164301ReactomeR-HSA-1643011Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164301.11MT-CO1Cytochrome c oxidase subunit 1Cytochrome c oxidase polypeptide IReactome DB_ID: 164314UniProt:P00395 MT-CO1MT-CO1COICOXIMTCO1FUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). As a newly synthesized protein, rapidly incorporates into a multi-subunit assembly intermediate in the inner membrane, called MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase) complex, whose core components are COA3/MITRAC12 and COX14. Within the MITRAC complex, interacts with COA3 and with SMIM20/MITRAC7; the interaction with SMIM20 stabilizes the newly synthesized MT-CO1 and prevents its premature turnover (PubMed:26321642). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948).DISEASE MT-CO1 may play a role in the pathogenesis of acquired idiopathic sideroblastic anemia, a disease characterized by inadequate formation of heme and excessive accumulation of iron in mitochondria. Mitochondrial iron overload may be attributable to mutations of mitochondrial DNA because these can cause respiratory chain dysfunction, thereby impairing reduction of ferric iron to ferrous iron. The reduced form of iron is essential to the last step of mitochondrial heme biosynthesis.SIMILARITY Belongs to the heme-copper respiratory oxidase family.UniProtP003951EQUAL513EQUALReactome Database ID Release 75164314Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164314ReactomeR-HSA-1643141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164314.111COX4I1Cytochrome c oxidase subunit IV isoform 1COX IV-1Cytochrome c oxidase polypeptide IVReactome DB_ID: 164305UniProt:P13073 COX4I1COX4I1COX4FUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunbit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with AFG1L (PubMed:26759378). Interacts with PHB2; the interaction decreases in absence of SPHK2 (By similarity).TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the cytochrome c oxidase IV family.UniProtP1307323EQUAL169EQUALReactome Database ID Release 75164305Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164305ReactomeR-HSA-1643051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164305.11COX7CCytochrome c oxidase polypeptide VIIcReactome DB_ID: 164306UniProt:P15954 COX7CCOX7CFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with RAB5IF (PubMed:31536960).SIMILARITY Belongs to the cytochrome c oxidase VIIc family.UniProtP1595417EQUAL63EQUALReactome Database ID Release 75164306Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164306ReactomeR-HSA-1643061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164306.11COX6B1Cytochrome c oxidase polypeptide VIbCytochrome c oxidase subunit AEDReactome DB_ID: 164299UniProt:P14854 COX6B1COX6B1COX6BFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).SIMILARITY Belongs to the cytochrome c oxidase subunit 6B family.UniProtP148542EQUAL86EQUALReactome Database ID Release 75164299Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164299ReactomeR-HSA-1642991Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164299.11COX5ACytochrome c oxidase polypeptide VaReactome DB_ID: 164308UniProt:P20674 COX5ACOX5AFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695). Interacts with AFG1L (PubMed:26759378). Interacts with RAB5IF (PubMed:31536960).DISEASE Mitochondrial complex IV deficiency is a rare condition caused by mutation in COX5A that lead to pulmonary arterial hypertension (PAH), failure to thrive and lactic acidemia.SIMILARITY Belongs to the cytochrome c oxidase subunit 5A family.UniProtP2067442EQUAL150EQUALReactome Database ID Release 75164308Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164308ReactomeR-HSA-1643081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164308.11COX7A2LCytochrome c oxidase subunit VIIa-related proteinCOX7a-related proteinReactome DB_ID: 164310UniProt:O14548 COX7A2LCOX7A2LCOX7ARCOX7RPFUNCTION Involved in the regulation of oxidative phosphorylation and energy metabolism (By similarity). Necessary for the assembly of mitochondrial respiratory supercomplex (By similarity).SUBUNIT Interacts with the mitochondrial respiratory supercomplex.INDUCTION By estrogen.SIMILARITY Belongs to the cytochrome c oxidase VIIa family.UniProtO1454856EQUAL114EQUALReactome Database ID Release 75164310Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164310ReactomeR-HSA-1643101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164310.11COX8ACytochrome c oxidase polypeptide VIIICytochrome c oxidase subunit 8-2Reactome DB_ID: 164313UniProt:P10176 COX8ACOX8ACOX8COX8LFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix.PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).SIMILARITY Belongs to the cytochrome c oxidase VIII family.UniProtP1017626EQUAL69EQUALReactome Database ID Release 75164313Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164313ReactomeR-HSA-1643131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164313.11NDUFA4NADH-ubiquinone oxidoreductase MLRQ subunit Complex I-MLRQCI-MLRQReactome DB_ID: 60617UniProt:O00483 NDUFA4NDUFA4FUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules unsing 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix (PubMed:22902835). NDUFA4 is required for complex IV maintenance (PubMed:22902835).SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:22902835, PubMed:23746447, PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (Probable). Interacts with RAB5IF (PubMed:31536960).MISCELLANEOUS During complex IV purifications dissociates from complex IV upon treatment with standard detergent DDM (decyl beta-D-maltoside) in high concentrations (PubMed:22902835, PubMed:23746447).SIMILARITY Belongs to the complex IV NDUFA4 subunit family.CAUTION Was initially believed to be a subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I).UniProtO004831EQUAL81EQUALReactome Database ID Release 7560617Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=60617ReactomeR-HSA-606171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-60617.11COX7BCytochrome c oxidase polypeptide VIIbReactome DB_ID: 164309UniProt:P24311 COX7BCOX7BFUNCTION Component of the cytochrome c oxidase, the last enzyme in the mitochondrial electron transport chain which drives oxidative phosphorylation. The respiratory chain contains 3 multisubunit complexes succinate dehydrogenase (complex II, CII), ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII) and cytochrome c oxidase (complex IV, CIV), that cooperate to transfer electrons derived from NADH and succinate to molecular oxygen, creating an electrochemical gradient over the inner membrane that drives transmembrane transport and the ATP synthase. Cytochrome c oxidase is the component of the respiratory chain that catalyzes the reduction of oxygen to water. Electrons originating from reduced cytochrome c in the intermembrane space (IMS) are transferred via the dinuclear copper A center (CU(A)) of subunit 2 and heme A of subunit 1 to the active site in subunit 1, a binuclear center (BNC) formed by heme A3 and copper B (CU(B)). The BNC reduces molecular oxygen to 2 water molecules using 4 electrons from cytochrome c in the IMS and 4 protons from the mitochondrial matrix (By similarity). Plays a role in proper central nervous system (CNS) development in vertebrates (PubMed:23122588).PATHWAY Energy metabolism; oxidative phosphorylation.SUBUNIT Component of the cytochrome c oxidase (complex IV, CIV), a multisubunit enzyme composed of 14 subunits. The complex is composed of a catalytic core of 3 subunits MT-CO1, MT-CO2 and MT-CO3, encoded in the mitochondrial DNA, and 11 supernumerary subunits COX4I1 (or COX4I2), COX5A, COX5B, COX6A1 (or COX6A2), COX6B1 (or COX6B2), COX6C, COX7A2 (or COX7A1), COX7B, COX7C, COX8A and NDUFA4, which are encoded in the nuclear genome (PubMed:30030519). The complex exists as a monomer or a dimer and forms supercomplexes (SCs) in the inner mitochondrial membrane with NADH-ubiquinone oxidoreductase (complex I, CI) and ubiquinol-cytochrome c oxidoreductase (cytochrome b-c1 complex, complex III, CIII), resulting in different assemblies (supercomplex SCI(1)III(2)IV(1) and megacomplex MCI(2)III(2)IV(2)) (PubMed:28844695).SIMILARITY Belongs to the cytochrome c oxidase VIIb family.UniProtP2431125EQUAL80EQUALReactome Database ID Release 75164309Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164309ReactomeR-HSA-1643091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164309.11Reactome Database ID Release 75164316Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164316ReactomeR-HSA-1643162Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-164316.2ComplexPortalCPX-6123GENE ONTOLOGYGO:0004129Reactome Database ID Release 75164322Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=164322Reactome Database ID Release 75163214Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163214ReactomeR-HSA-1632145Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163214.515223Pubmed1977Proton pump coupled to cytochrome c oxidase in mitochondriaWikstrom, MKNature 266:271-316760263Pubmed2006Assembly of mitochondrial cytochrome c-oxidase, a complicated and highly regulated cellular processFontanesi, FlaviaSoto, Ileana CHorn, DarrylBarrientos, AntoniAm. J. Physiol., Cell Physiol. 291:C1129-4711340051Pubmed2001Structures and proton-pumping strategies of mitochondrial respiratorySchultz, BEChan, SIAnnu Rev Biophys Biomol Struct 30:23-6517298220Pubmed2006Biogenesis of eukaryotic cytochrome c oxidaseStiburek, LHansikova, HTesarova, MCerna, LZeman, JPhysiol Res 55:S27-4123746447Pubmed2013NDUFA4 mutations underlie dysfunction of a cytochrome c oxidase subunit linked to human neurological diseasePitceathly, Robert D SRahman, SWedatilake, YehaniPolke, James MCirak, SebahattinFoley, A ReghanSailer, AnnaHurles, Matthew EStalker, JimHargreaves, IainWoodward, Cathy ESweeney, Mary GMuntoni, FrancescoHoulden, HenryTaanman, Jan-WillemHanna, Michael GCell Rep 3:1795-80522902835Pubmed2012NDUFA4 is a subunit of complex IV of the mammalian electron transport chainBalsa, EduardoMarco, RicardoPerales-Clemente, EsterSzklarczyk, RadekCalvo, EnriqueLandázuri, Manuel OEnríquez, José AntonioCell Metab. 16:378-867979252Pubmed1994Energy transduction by cytochrome complexes in mitochondrial and bacterialTrumpower, BLGennis, RBAnnu Rev Biochem 63:675-71621958598Pubmed2012Biogenesis and assembly of eukaryotic cytochrome c oxidase catalytic coreSoto, Ileana CFontanesi, FlaviaLiu, JingjingBarrientos, AntoniBiochim. Biophys. Acta 1817:883-97GENE ONTOLOGYGO:0006123ACTIVATIONReactome Database ID Release 755336167Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336167ReactomeR-HSA-53361671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336167.1Converted from EntitySet in ReactomeCOX11,14,16,18,20Reactome DB_ID: 5336143COX11Cytochrome c oxidase assembly protein COX11, mitochondrialCOX11_HUMANReactome DB_ID: 5336155UniProt:Q9Y6N1 COX11COX11FUNCTION Exerts its effect at some terminal stage of cytochrome c oxidase synthesis, probably by being involved in the insertion of the copper B into subunit I.SUBUNIT Interacts with CNNM4/ACDP4.TISSUE SPECIFICITY Ubiquitous.SIMILARITY Belongs to the COX11/CtaG family.UniProtQ9Y6N11EQUAL276EQUALReactome Database ID Release 755336155Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336155ReactomeR-HSA-53361551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336155.1COX14Cytochrome c oxidase assembly protein COX14COX14_HUMANReactome DB_ID: 5336163UniProt:Q96I36 COX14COX14C12orf62FUNCTION Core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly. Requires for coordination of the early steps of cytochrome c oxidase assembly with the synthesis of MT-CO1.SUBUNIT Along with COA3, core component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex.DISEASE Defects in COX14 may be a cause of a mitochondrial disorder presenting with severe congenital lactic acidosis and dysmorphic features associated with a COX assembly defect. Other features include brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.UniProtQ96I361EQUAL57EQUALReactome Database ID Release 755336163Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336163ReactomeR-HSA-53361631Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336163.1COX16Cytochrome c oxidase assembly protein COX16 homolog, mitochondrialCOX16_HUMANReactome DB_ID: 5336135UniProt:Q9P0S2 COX16COX16C14orf112HSPC203PTD019FUNCTION Required for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:29355485, PubMed:29381136). Promotes the insertion of copper into the active site of cytochrome c oxidase subunit II (MT-CO2/COX2) (PubMed:29355485, PubMed:29381136). Interacts specifically with newly synthesized MT-CO2/COX and its copper center-forming metallochaperones SCO1, SCO2 and COA6 (PubMed:29381136). Probably facilitates MT-CO2/COX2 association with the MITRAC assembly intermediate containing MT-CO1/COX1, thereby participating in merging the MT-CO1/COX1 and MT-CO2/COX2 assembly lines (PubMed:29381136).SUBUNIT Associates with the MITRAC complex (PubMed:29381136). Interacts with MT-CO2/COX; specifically interacts with newly synthesized MT-CO2/COX (PubMed:29355485, PubMed:29381136). Interacts with SCO1, SCO2 and COA6 (PubMed:29381136).TISSUE SPECIFICITY Widely expressed. Expressed at higher level in skeletal muscle, heart and liver.MISCELLANEOUS No COX16 mutations have been detected in patients with cytochrome c oxidase (COX) deficiency.SIMILARITY Belongs to the COX16 family.UniProtQ9P0S21EQUAL106EQUALReactome Database ID Release 755336135Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336135ReactomeR-HSA-53361351Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336135.1COX20Cytochrome c oxidase protein 20 homologCOX20_HUMANReactome DB_ID: 5336169UniProt:Q5RI15 COX20COX20FAM36AFUNCTION Essential for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:23125284). Acts as a chaperone in the early steps of cytochrome c oxidase subunit II (MT-CO2/COX2) maturation, stabilizing the newly synthesized protein and presenting it to metallochaperones SCO1/2 which in turn facilitates the incorporation of the mature MT-CO2/COX2 into the assembling CIV holoenzyme (PubMed:24403053).SUBUNIT Found in a complex with TMEM177, COA6, MT-CO2/COX2, COX18, SCO1 and SCO2. Interacts with SCO1, SCO2 and COA6 in a MT-CO2/COX2- and COX18-dependent manner (PubMed:29154948, PubMed:24403053, PubMed:28330871). Interacts with COX18 in a MT-CO2/COX2-dependent manner (PubMed:28330871). Interacts with MT-CO2/COX2 (PubMed:29154948, PubMed:24403053, PubMed:23125284, PubMed:28330871). Interacts with TMEM177 (PubMed:29154948).SIMILARITY Belongs to the COX20 family.UniProtQ5RI151EQUAL118EQUALReactome Database ID Release 755336169Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336169ReactomeR-HSA-53361691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336169.1COX18Mitochondrial inner membrane protein COX18COX18_HUMANReactome DB_ID: 5216190UniProt:Q8N8Q8 COX18COX18OXA1L2FUNCTION Mitochondrial membrane insertase required for the translocation of the C-terminus of cytochrome c oxidase subunit II (MT-CO2/COX2) across the mitochondrial inner membrane. Plays a role in MT-CO2/COX2 maturation following the COX20-mediated stabilization of newly synthesized MT-CO2/COX2 protein and before the action of the metallochaperones SCO1/2. Essential for the assembly and stability of the mitochondrial respiratory chain complex IV (also known as cytochrome c oxidase).SUBUNIT Found in a complex with TMEM177, COA6, MT-CO2/COX2, COX20, SCO1 and SCO2 (PubMed:29154948). Interacts transiently with MT-CO2/COX2 during its maturation (PubMed:28330871). Interacts with COX20 in a MT-CO2/COX2-dependent manner (PubMed:28330871).SIMILARITY Belongs to the OXA1/ALB3/YidC family.UniProtQ8N8Q81EQUAL333EQUALReactome Database ID Release 755216190Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5216190ReactomeR-HSA-52161901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5216190.1Reactome Database ID Release 755336143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336143ReactomeR-HSA-53361431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336143.1ACTIVATIONReactome Database ID Release 755566489Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5566489ReactomeR-HSA-55664891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5566489.1Converted from EntitySet in ReactomeCOX ancilliary proteinsReactome DB_ID: 5566488LRPPRCLeucine-rich PPR motif-containing protein, mitochondrialLPPRC_HUMANReactome DB_ID: 5336174UniProt:P42704 LRPPRCLRPPRCLRP130FUNCTION May play a role in RNA metabolism in both nuclei and mitochondria. In the nucleus binds to HNRPA1-associated poly(A) mRNAs and is part of nmRNP complexes at late stages of mRNA maturation which are possibly associated with nuclear mRNA export. May bind mature mRNA in the nucleus outer membrane. In mitochondria binds to poly(A) mRNA. Plays a role in translation or stability of mitochondrially encoded cytochrome c oxidase (COX) subunits. May be involved in transcription regulation. Cooperates with PPARGC1A to regulate certain mitochondrially encoded genes and gluconeogenic genes and may regulate docking of PPARGC1A to transcription factors. Seems to be involved in the transcription regulation of the multidrug-related genes MDR1 and MVP. Part of a nuclear factor that binds to the invMED1 element of MDR1 and MVP gene promoters. Binds single-stranded DNA (By similarity).SUBUNIT Interacts with CECR2, HEBP2, MAP1S and UXT. Interacts with PPARGC1A. Interacts with FOXO1 (By similarity). Component of mRNP complexes associated with HNRPA1.TISSUE SPECIFICITY Expressed ubiquitously. Expression is highest in heart, skeletal muscle, kidney and liver, intermediate in brain, non-mucosal colon, spleen and placenta, and lowest in small intestine, thymus, lung and peripheral blood leukocytes.UniProtP4270460EQUAL1394EQUALReactome Database ID Release 755336174Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336174ReactomeR-HSA-53361741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336174.1SCO1Protein SCO1 homolog, mitochondrialSCO1_HUMANReactome DB_ID: 5336170UniProt:O75880 SCO1SCO1SCOD1FUNCTION Copper metallochaperone essential for the maturation of cytochrome c oxidase subunit II (MT-CO2/COX2). Not required for the synthesis of MT-CO2/COX2 but plays a crucial role in stabilizing MT-CO2/COX2 during its subsequent maturation. Involved in transporting copper to the Cu(A) site on MT-CO2/COX2 (PubMed:15659396, PubMed:16735468, PubMed:17189203, PubMed:19336478, PubMed:15229189). Plays an important role in the regulation of copper homeostasis by controlling the abundance and cell membrane localization of copper transporter CTR1 (By similarity).SUBUNIT Homodimer (PubMed:16735468, PubMed:15229189). Interacts with COA6 (PubMed:26160915). Found in a complex with TMEM177, COX20, COA6, MT-CO2/COX2, COX18 and SCO2 (PubMed:29154948). Interacts with TMEM177 in a COX20-dependent manner (PubMed:29154948). Interacts with COX20 in a MT-CO2/COX2- and COX18-dependent manner (PubMed:29154948, PubMed:24403053, PubMed:28330871). Interacts with COX16 (PubMed:29381136).TISSUE SPECIFICITY Predominantly expressed in tissues characterized by high rates of oxidative phosphorylation (OxPhos), including muscle, heart, and brain.SIMILARITY Belongs to the SCO1/2 family.UniProtO758801EQUAL301EQUALReactome Database ID Release 755336170Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336170ReactomeR-HSA-53361701Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336170.1SURF1Surfeit locus protein 1SURF1_HUMANReactome DB_ID: 5336159UniProt:Q15526 SURF1SURF1SURF-1FUNCTION Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, that regulates cytochrome c oxidase assembly.SUBUNIT Component of the MITRAC (mitochondrial translation regulation assembly intermediate of cytochrome c oxidase complex) complex, the core components of this complex being COA3/MITRAC12 and COX14. Interacts with COA3.DEVELOPMENTAL STAGE Expressed in the fetus (at protein level).SIMILARITY Belongs to the SURF1 family.UniProtQ155261EQUAL300EQUALReactome Database ID Release 755336159Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336159ReactomeR-HSA-53361591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336159.1TACO1Translational activator of cytochrome c oxidase 1TACO1_HUMANReactome DB_ID: 5336153UniProt:Q9BSH4 TACO1TACO1CCDC44PRO0477FUNCTION Acts as a translational activator of mitochondrially-encoded cytochrome c oxidase 1.SIMILARITY Belongs to the TACO1 family.UniProtQ9BSH41EQUAL297EQUALReactome Database ID Release 755336153Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336153ReactomeR-HSA-53361531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336153.1Reactome Database ID Release 755566488Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5566488ReactomeR-HSA-55664881Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5566488.1ACTIVATIONReactome Database ID Release 755336136Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5336136ReactomeR-HSA-53361361Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5336136.1COX19Cytochrome c oxidase assembly protein COX19COX19_HUMANReactome DB_ID: 6800071UniProt:Q49B96 COX19COX19FUNCTION Required for the transduction of an SCO1-dependent redox signal from the mitochondrion to ATP7A to regulate cellular copper homeostasis (PubMed:23345593). May be required for the assembly of mitochondrial cytochrome c oxidase (By similarity).SUBUNIT Interacts with CHCHD4/MIA40 forming transient intermolecular disulfide bridges.TISSUE SPECIFICITY Ubiquitously expressed. Highly expressed in skeletal muscle.SIMILARITY Belongs to the COX19 family.UniProtQ49B962EQUAL90EQUALReactome Database ID Release 756800071Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6800071ReactomeR-HSA-68000711Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6800071.1LEFT-TO-RIGHTTP53 binds the RRM2B geneTP53 (p53) binds the p53-binding site in the first intron of RRM2B (p53R2) gene, which encodes a subunit of the ribonucleotide reductase complex (Tanaka et al. 2000). RRM2B is also regulated by TP73 (p73), a p53 family member (Nakano et al. 2000).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23RRM2B Genep53R2 GeneReactome DB_ID: 5632883ENSEMBL:ENSG00000048392 RRM2BRRM2BP53R2ENSEMBLENSG00000048392Reactome Database ID Release 755632883Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632883ReactomeR-HSA-56328831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632883.1TP53 Tetramer:RRM2B GeneReactome DB_ID: 563288611Reactome Database ID Release 755632886Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632886ReactomeR-HSA-56328861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632886.1Reactome Database ID Release 755632887Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632887ReactomeR-HSA-56328874Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632887.410716435Pubmed2000A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damageTanaka, HiroshiArakawa, HirofumiYamaguchi, TatsuyaShiraishi, KenjiFukuda, SeisukeMatsui, KunikoTakei, YoshikiNakamura, YusukeNature 404:42-4910980602Pubmed2000A ribonucleotide reductase gene is a transcriptional target of p53 and p73Nakano, KBálint, EAshcroft, MVousden, K HOncogene 19:4283-9LEFT-TO-RIGHTTP53 stimulates transcription of RRM2B geneTP53 (p53) directly stimulates transcription of RRM2B gene (p53R2), which encodes a critical subunit of the ribonucleotide reductase complex (Tanaka et al. 2000), responsible for de novo conversion of ribonucleotides (NTPs) to deoxyribonucleotides (dNTPs). This regulation provides a direct mechanism through which TP53 contributes to DNA synthesis/repair. Mutations in RRM2B gene cause severe mitochondrial DNA depletion (Bourdon et al. 2007, Kulawiec et al. 2009).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23RRM2Bribonucleotide reductase M2B (TP53 inducible)Reactome DB_ID: 111792UniProt:Q7LG56 RRM2BRRM2BP53R2FUNCTION Plays a pivotal role in cell survival by repairing damaged DNA in a p53/TP53-dependent manner. Supplies deoxyribonucleotides for DNA repair in cells arrested at G1 or G2. Contains an iron-tyrosyl free radical center required for catalysis. Forms an active ribonucleotide reductase (RNR) complex with RRM1 which is expressed both in resting and proliferating cells in response to DNA damage.PATHWAY Genetic information processing; DNA replication.SUBUNIT Heterotetramer with large (RRM1) subunit. Interacts with p53/TP53. Interacts with RRM1 in response to DNA damage.TISSUE SPECIFICITY Widely expressed at a high level in skeletal muscle and at a weak level in thymus. Expressed in epithelial dysplasias and squamous cell carcinoma.INDUCTION In response to DNA damage in a wild-type p53/TP53-dependent manner.SIMILARITY Belongs to the ribonucleoside diphosphate reductase small chain family.UniProtQ7LG561EQUAL351EQUALReactome Database ID Release 75111792Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=111792ReactomeR-HSA-1117922Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-111792.2Reactome Database ID Release 755632892Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632892ReactomeR-HSA-56328925Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632892.519439913Pubmed2009p53 regulates mtDNA copy number and mitocheckpoint pathwayKulawiec, MariolaAyyasamy, VanniarajanSingh, Keshav KJ Carcinog 8:817486094Pubmed2007Mutation of RRM2B, encoding p53-controlled ribonucleotide reductase (p53R2), causes severe mitochondrial DNA depletionBourdon, AliceMinai, LimorSerre, ValérieJais, Jean-PhilippeSarzi, EmmanuelleAubert, SophieChrétien, Dominiquede Lonlay, PascalePaquis-Flucklinger, VeroniqueArakawa, HirofumiNakamura, YusukeMunnich, ARötig, AgnèsNat. Genet. 39:776-80ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 755632893Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632893ReactomeR-HSA-56328931Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632893.1LEFT-TO-RIGHTTP53 binds the GLS2 promoterThe mitochondrial glutaminase GLS2 gene possesses two putative p53-binding sites in its promoter and one putative p53 binding site in the first intron. TP53 was demonstrated to bind to p53-response elements in the promoter but not intron 1 of GLS2 (Hu et al. 2010, Suzuki et al. 2010).Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23GLS2 GeneReactome DB_ID: 5632920ENSEMBL:ENSG00000135423 GLS2GLS2GAENSEMBLENSG00000135423Reactome Database ID Release 755632920Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632920ReactomeR-HSA-56329201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632920.1TP53 Tetramer:GLS2 GeneReactome DB_ID: 563291911Reactome Database ID Release 755632919Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632919ReactomeR-HSA-56329191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632919.1Reactome Database ID Release 755632914Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632914ReactomeR-HSA-56329144Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632914.420378837Pubmed2010Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant functionHu, WenweiZhang, CenWu, RuiSun, YvonneLevine, ArnoldFeng, ZhaohuiProc. Natl. Acad. Sci. U.S.A. 107:7455-6020351271Pubmed2010Phosphate-activated glutaminase (GLS2), a p53-inducible regulator of glutamine metabolism and reactive oxygen speciesSuzuki, SawakoTanaka, TomoakiPoyurovsky, Masha VNagano, HidekazuMayama, TakafumiOhkubo, ShuichiLokshin, MariaHosokawa, HiroyukiNakayama, ToshinoriSuzuki, YutakaSugano, SumioSato, EiichiNagao, ToshitakaYokote, KoutaroTatsuno, IchiroPrives, CarolProc. Natl. Acad. Sci. U.S.A. 107:7461-6LEFT-TO-RIGHTTP53 stimulates GLS2 transcriptionTP53 (p53) directly stimulates transcription of mitochondrial glutaminase GLS2 under non-stress and stress conditions. Increased GLS2 levels lead to increased production of glutamate and alpha-ketoglutarate, increased mitochondrial respiration rate, and reduced ROS (reactive oxygen species) load through enhanced glutathione reduction (Hu et al. 2010).<p>Elevated GLS2 was associated with lower levels of intracellular ROS and a decrease in DNA oxidation. GLS2 knockdown resulted in higher ROS levels and was associated with stimulation of p53-induced cell death (Suzuki et al. 2010). Authored: Orlic-Milacic, Marija, 2014-12-23Reviewed: Hwang, Paul M, 2014-12-30Reviewed: Kang, Ju-Gyeong, 2014-12-30Reviewed: Wang, Ping-yuan, 2014-12-30Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: Orlic-Milacic, Marija, 2014-12-23GLS2 dimerReactome DB_ID: 507858GLS2glutaminase 2Glutaminase, liver isoform, mitochondrial precursor Reactome DB_ID: 70610UniProt:Q9UI32 GLS2GLS2GAFUNCTION Plays an important role in the regulation of glutamine catabolism. Promotes mitochondrial respiration and increases ATP generation in cells by catalyzing the synthesis of glutamate and alpha-ketoglutarate. Increases cellular anti-oxidant function via NADH and glutathione production. May play a role in preventing tumor proliferation.SUBUNIT Homotetramer, dimer of dimers (Probable). Does not assemble into higher oligomers (By similarity). Interacts with the PDZ domain of the syntrophin SNTA1. Interacts with the PDZ domain of TAX1BP3 (PubMed:11163757).TISSUE SPECIFICITY Highly expressed in liver. Expressed in brain and pancreas. Not observed in heart, placenta, lung, skeletal muscle and kidney. Expression is significantly reduced in hepatocellular carcinomas.INDUCTION Up-regulated by P53 (at protein and mRNA level) under both stressed and non-stressed conditions.SIMILARITY Belongs to the glutaminase family.UniProtQ9UI3215EQUAL602EQUALReactome Database ID Release 7570610Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70610ReactomeR-HSA-706101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70610.12Reactome Database ID Release 75507858Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=507858ReactomeR-HSA-5078581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-507858.1Reactome Database ID Release 755632924Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632924ReactomeR-HSA-56329244Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632924.4ACTIVATIONactiveUnit: #Complex1Reactome Database ID Release 755632932Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632932ReactomeR-HSA-56329321Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5632932.1LEFT-TO-RIGHT3.5.1.2glutamine + H2O => glutamate + NH4+ [GLS]Mitochondrial glutaminase (GLS) catalyzes the hydrolysis of glutamine to yield glutamate and ammonia. Two GLS enzymes have been identified, one abundantly expressed in the liver (GLS - Elgadi et al. 1999) and one abundantly expressed in kidney (GLS2 - Gomez-Fabre et al. 2000). Their biochemical properties are similar. The enzymes are inferred to function as dimers based on unpublished crystallographic data for GLS (PDB 3CZD) and studies of glutaminase enzyme purified from Ehrlich Ascites cells (Quesada et al. 1988).Authored: D'Eustachio, Peter, 2003-05-04Reviewed: Inga, Alberto, 2016-02-04Reviewed: Zaccara, Sara, 2016-02-04Edited: D'Eustachio, P, 2010-04-30L-GlnL-2-Aminoglutaramic acidL-glutamine zwitterionL-glutamineReactome DB_ID: 113522L-glutamine zwitterion [ChEBI:58359]L-glutamine zwitterion146.14450(2S)-5-amino-2-ammonio-5-oxopentanoateNC(=O)CC[C@H]([NH3+])C([O-])=OC5H10N2O3(2S)-5-amino-2-azaniumyl-5-oxopentanoateL-glutamineZDXPYRJPNDTMRX-VKHMYHEASA-NInChI=1S/C5H10N2O3/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H2,7,8)(H,9,10)/t3-/m0/s1ChEBICHEBI:58359Reactome Database ID Release 75113522Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113522ReactomeR-ALL-1135224Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113522.4COMPOUNDC00064NH4+ammoniumReactome DB_ID: 113561ammonium [ChEBI:28938]ammoniumChEBICHEBI:28938Reactome Database ID Release 75113561Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113561ReactomeR-ALL-1135613Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113561.3COMPOUNDC01342GluL-GluL-glutamate(1-)L-glutamic acidL-GlutamateL-Glutaminic acidReactome DB_ID: 113552L-glutamate(1-) [ChEBI:29985]L-glutamate(1-)L-glutamic acid, ion(1-)[NH3+][C@@H](CCC([O-])=O)C([O-])=OWHUUTDBJXJRKMK-VKHMYHEASA-MC5H8NO4146.12136(2S)-2-ammoniopentanedioatehydrogen L-glutamateL-glutamateL-glutamic acid monoanionInChI=1S/C5H9NO4/c6-3(5(9)10)1-2-4(7)8/h3H,1-2,6H2,(H,7,8)(H,9,10)/p-1/t3-/m0/s1ChEBICHEBI:29985Reactome Database ID Release 75113552Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113552ReactomeR-ALL-1135525Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-113552.5COMPOUNDC00025ACTIVATIONConverted from EntitySet in ReactomeGLS dimersReactome DB_ID: 507859GLS dimerReactome DB_ID: 507860GLSglutaminaseGlutaminase, kidney isoform, mitochondrial precursor Reactome DB_ID: 70607UniProt:O94925 GLSGLSGLS1KIAA0838FUNCTION Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine. Plays a role in maintaining acid-base homeostasis. Regulates the levels of the neurotransmitter glutamate, the main excitatory neurotransmitter in the brain (PubMed:30575854, PubMed:30239721, PubMed:30970188).ACTIVITY REGULATION Isoform 1 and isoform 3 are activated by phosphate. Inhibited by BPTES. BPTES binds between subunits and favors dissociation of the tetramer into dimers (PubMed:22049910). Inhibited by 6-diazo-5-oxo-L-norleucine (DON) (PubMed:24451979). Enzyme activity is stimulated by phosphorylation (PubMed:22538822).SUBUNIT Homotetramer, dimer of dimers (PubMed:22538822, PubMed:26988803, PubMed:28526749, PubMed:29317493). The tetramers can assemble into rod-like oligomers (in vitro), but the physiological significance of this is not clear (By similarity). Interacts with RAF1 and MAP2K2 (PubMed:22538822). Interacts with ATCAY; the interaction is direct and may control GLS localization, negatively regulating its activity.TISSUE SPECIFICITY Isoform 1 and isoform 3 are detected in brain cortex. Isoform 3 is highly expressed in astrocytoma, ganglioglioma and ependymoma. Isoform 1 is highly expressed in brain and kidney, but not detected in liver. Isoform 3 is highly expressed in heart and pancreas, detected at lower levels in placenta, lung, pancreas and kidney, but is not detected in liver. Isoform 2 is expressed in cardiac and skeletal muscle.DOMAIN The C-terminal ANK repeats prevent the assembly of the supra-tetrameric filaments.DOMAIN A highly mobile activation loop at the dimer-dimer interface is important for enzyme activity.PTM Synthesized as a 74-kDa cytosolic precursor which is proteolytically processed by the mitochondrial-processing peptidase (MPP) via a 72-kDa intermediate to yield the mature mitochondrial 68- and 65-kDa subunits.SIMILARITY Belongs to the glutaminase family.CAUTION Isoform 3 is predicted to be expressed at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Contrary to expectations, it has been shown to be well expressed, and the encoded protein is detected in mitochondria (PubMed:11015561, PubMed:17940881, PubMed:22228304).UniProtO9492517EQUAL669EQUALReactome Database ID Release 7570607Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=70607ReactomeR-HSA-706071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-70607.12Reactome Database ID Release 75507860Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=507860ReactomeR-HSA-5078601Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-507860.1Reactome Database ID Release 75507859Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=507859ReactomeR-HSA-5078591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-507859.1GENE ONTOLOGYGO:0004359Reactome Database ID Release 75