BioPAX pathway converted from "Regulation of TP53 Activity through Association with Co-factors" in the Reactome database. Regulation of TP53 Activity through Association with Co-factors Association of TP53 (p53) with various transcriptional co-factors can promote, inhibit or provide specificity towards either transcription of cell cycle arrest genes or transcription of cell death genes. Binding of the zinc finger protein ZNF385A (HZF), which is a transcriptional target of TP53, stimulates transcription of cell cycle arrest genes, such as CDKN1A (Das et al. 2007). Binding of POU4F1 (BRN3A) to TP53 also stimulates transcription of cell cycle arrest genes while inhibiting transcription of pro-apoptotic genes (Budhram-Mahadeo et al. 1999, Hudson et al. 2005).<p>Binding of ASPP family proteins PPP1R13B (ASPP1) or TP53BP2 (ASPP2) to TP53 stimulates transcription of pro-apoptotic TP53 targets (Samuels-Lev et al. 2001, Bergamaschi et al. 2004). Binding of the ASPP family member PPP1R13L (iASSP) inhibits TP53-mediated activation of pro-apoptotic genes probably by interfering with binding of stimulatory ASPPs to TP53 (Bergamaschi et al. 2003). Transcription of pro-apoptotic genes is also stimulated by binding of TP53 to POU4F2 (BRN3B) (Budrham-Mahadeo et al. 2006, Budhram-Mahadeo et al. 2014) or to hCAS/CSE1L (Tanaka et al. 2007).<p>Binding of co-factors to TP53 can also affect protein stability. For example, PHF20 binds to TP53 dimethylated on lysine residues K370 and K382 by unidentified protein lysine methyltransferase(s) and interferes with MDM2 binding, resulting in prolonged TP53 half-life (Cui et al. 2012). Long noncoding RNAs can contribute to p53-dependent transcriptional responses (Huarte et al. 2010). For a general review on this topic, see Espinosa 2008, Beckerman and Prives 2010, Murray-Zmijewski et al. 2008, An et al. 2004 and Barsotti and Prives 2010. Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 LEFT-TO-RIGHT TP53 binds ZNF385A gene TP53 (p53) binds to at least one of the three putative p53 response elements in the promoter of the human ZNF385A (HZF) gene (Das et al. 2007). In the mouse Znf385a gene, the p53 response element is in the first intron and also binds Tp53 (Sugimoto et al. 2006). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 ZNF385A Gene Reactome DB_ID: 6803422 nucleoplasm GENE ONTOLOGY GO:0005654 ENSEMBL:ENSG00000161642 ZNF385A ZNF385A HZF RZF ZNF385 Homo sapiens NCBI Taxonomy 9606 ENSEMBL ENSG00000161642 Reactome Database ID Release 81 6803422 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803422 Reactome R-HSA-6803422 1 Reactome stable identifier. Use this 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-6803422.1 Reactome http://www.reactome.org p-S15,S20-TP53 Tetramer Reactome DB_ID: 3222171 p-S15,S20-TP53 Reactome DB_ID: 69683 UniProt:P04637 TP53 TP53 P53 FUNCTION 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, 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). Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation (PubMed:21597459). Interacts with S100A4; this interaction promotes TP53 degradation (PubMed:23752197, PubMed:32442400). Interacts with BANP (By similarity). Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis (PubMed:25168243).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.SUBUNIT (Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the cytoplasmic localization of TP53 thereby decreasing its transcriptional activity.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. Acetylation of Lys-382 by EP300. 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 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). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation (PubMed:21597459).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.CAUTION Interaction with BANP was reported to enhance phosphorylation on Ser-15 upon ultraviolet irradiation (PubMed:15701641). However, the publication has been retracted due to image duplication and manipulation. Interaction with BANP has been confirmed in mouse studies (By similarity). Phosphorylation at Ser-15 has been confirmed by other studies (PubMed:10570149, PubMed:11554766, PubMed:16219768, PubMed:15866171, PubMed:17317671, PubMed:17954561, PubMed:20959462, PubMed:25772236). Its nuclear and cytoplasmic localization has been confirmed by other studies (PubMed:15340061, PubMed:17170702, PubMed:19011621, PubMed:21597459, PubMed:22726440, PubMed:17591690, PubMed:18206965). UniProt P04637 20 EQUAL O-phospho-L-serine MOD MOD:00046 15 EQUAL 1 EQUAL 393 EQUAL Reactome Database ID Release 81 69683 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69683 Reactome R-HSA-69683 1 Reactome stable identifier. Use this 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-69683.1 4 Reactome Database ID Release 81 3222171 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222171 Reactome R-HSA-3222171 1 Reactome stable identifier. Use this 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-3222171.1 p-S15,S20-TP53 Tetramer:ZNF385A Gene Reactome DB_ID: 6803418 1 1 Reactome Database ID Release 81 6803418 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803418 Reactome R-HSA-6803418 1 Reactome stable identifier. Use this 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-6803418.1 Reactome Database ID Release 81 6803425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803425 Reactome R-HSA-6803425 2 Reactome stable identifier. Use this 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-6803425.2 16382142 Pubmed 2006 Hzf, a p53-responsive gene, regulates maintenance of the G2 phase checkpoint induced by DNA damage Sugimoto, Masataka Gromley, Adam Sherr, Charles J Mol. Cell. Biol. 26:502-12 17719541 Pubmed 2007 Hzf Determines cell survival upon genotoxic stress by modulating p53 transactivation Das, Sanjeev Raj, Lakshmi Zhao, Bo Kimura, Yuki Bernstein, Alan Aaronson, Stuart A Lee, Sam W Cell 130:624-37 LEFT-TO-RIGHT TP53 stimulates ZNF385A transcription Binding of TP53 (p53) to the p53 response element(s) in the promoter of the ZNF385A (HZF) gene stimulates ZNF385A transcription (Das et al. 2007). TP53-mediated induction of ZNF385A is conserved in mouse (Sugimoto et al. 2006, Das et al. 2007). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 HZF ZNF385A Zinc finger protein 385A Retinal zinc finger protein Hematopoietic zinc finger protein HZF ZNF385 Reactome DB_ID: 6803421 UniProt:Q96PM9 ZNF385A ZNF385A HZF RZF ZNF385 FUNCTION RNA-binding protein that affects the localization and the translation of a subset of mRNA. May play a role in adipogenesis through binding to the 3'-UTR of CEBPA mRNA and regulation of its translation. Targets ITPR1 mRNA to dendrites in Purkinje cells, and may regulate its activity-dependent translation. With ELAVL1, binds the 3'-UTR of p53/TP53 mRNAs to control their nuclear export induced by CDKN2A. Hence, may regulate p53/TP53 expression and mediate in part the CDKN2A anti-proliferative activity. May also bind CCNB1 mRNA. Alternatively, may also regulate p53/TP53 activity through direct protein-protein interaction. Interacts with p53/TP53 and promotes cell-cycle arrest over apoptosis enhancing preferentially the DNA binding and transactivation of p53/TP53 on cell-cycle arrest target genes over proapoptotic target genes. May also regulate the ubiquitination and stability of CDKN1A promoting DNA damage-induced cell cycle arrest. Also plays a role in megakaryocytes differentiation.SUBUNIT Interacts with ELAVL1; the interaction is indirect, mRNA-dependent and may regulate p53/TP53 expression (By similarity). Interacts with p53/TP53; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest.TISSUE SPECIFICITY Expressed predominantly in the retina.INDUCTION Up-regulated by p53/TP53 in response to DNA damage and oxidative stress.PTM Ubiquitinated upon prolonged exposure to genotoxic stress, which leads to proteasomal degradation of ZNF385A and releases p53/TP53 from cell-cycle arrest target gene promoters. UniProt Q96PM9 Reactome Database ID Release 81 6803421 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803421 Reactome R-HSA-6803421 1 Reactome stable identifier. Use this 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-6803421.1 Reactome Database ID Release 81 6803437 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803437 Reactome R-HSA-6803437 3 Reactome stable identifier. Use this 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-6803437.3 ACTIVATION activeUnit: #Complex1 Reactome Database ID Release 81 6803537 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803537 Reactome R-HSA-6803537 1 Reactome stable identifier. Use this 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-6803537.1 LEFT-TO-RIGHT TP53 binds ZNF385A ZNF385A (HZF) forms a complex with TP53 (p53), interacting with the DNA binding domain of TP53. The complex of TP53 and ZNF385A associates with p53 response elements of cell cycle arrest genes, such as CDKN1A (p21) and stimulates their transcription. Under prolonged stress, ZNF385A undergoes ubiquitination and proteasome-mediated degradation, which coincides with expression of TP53-regulated pro-apoptotic genes (Das et al. 2007). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 p-S15,S20-TP53 Tetramer:ZNF385A Reactome DB_ID: 6803718 1 1 Reactome Database ID Release 81 6803718 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803718 Reactome R-HSA-6803718 1 Reactome stable identifier. Use this 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-6803718.1 Reactome Database ID Release 81 6803719 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6803719 Reactome R-HSA-6803719 2 Reactome stable identifier. Use this 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-6803719.2 LEFT-TO-RIGHT TP53 binds POU4F1 TP53 (p53) forms a complex with a transcription factor POU4F1 (BRN3A). This interaction involves the POU domain of POU4F1. Binding of TP53 to POU4F1 modulates the transcriptional activity of both proteins, but the exact mechanism has not been elucidated. TP53 inhibits POU4F1-mediated induction of BCL2 transcription (Budhram-Mahadeo et al. 1999). POU4F1 inhibits TP53-mediated induction of BAX and NOXA, but enhances TP53-mediated induction of CDKN1A (p21) (Budhram-Mahadeo et al. 2002, Hudson et al. 2005). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 RDC1 POU4F1 POU domain, class 4, transcription factor 1 BRN3A Brn-3A Brain-3A Brain-specific homeobox/POU domain protein 3A Oct-T1 Homeobox/POU domain protein RDC-1 Reactome DB_ID: 6804391 UniProt:Q01851 POU4F1 POU4F1 BRN3A RDC1 FUNCTION Multifunctional transcription factor with different regions mediating its different effects. Acts by binding (via its C-terminal domain) to sequences related to the consensus octamer motif 5'-ATGCAAAT-3' in the regulatory regions of its target genes. Regulates the expression of specific genes involved in differentiation and survival within a subset of neuronal lineages. It has been shown that activation of some of these genes requires its N-terminal domain, maybe through a neuronal-specific cofactor. Ativates BCL2 expression and protects neuronal cells from apoptosis (via the N-terminal domain). Induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins. Exerts its major developmental effects in somatosensory neurons and in brainstem nuclei involved in motor control. Stimulates the binding affinity of the nuclear estrogene receptor ESR1 to DNA estrogen response element (ERE), and hence modulates ESR1-induced transcriptional activity. May positively regulate POU4F2 and POU4F3. Regulates dorsal root ganglion sensory neuron specification and axonal projection into the spinal cord. Plays a role in TNFSF11-mediated terminal osteoclast differentiation. Negatively regulates its own expression interacting directly with a highly conserved autoregulatory domain surrounding the transcription initiation site.SUBUNIT Interacts (via N-terminus) with RIT2; the interaction controls POU4F1 transactivation activity on some neuronal target genes. Isoform 1 interacts with POU4F2; this interaction inhibits both POU4F1 DNA-binding and transcriptional activities. Isoform 1 interacts (C-terminus) with ESR1 (via DNA-binding domain); this interaction decreases the estrogen receptor ESR1 transcriptional activity in a DNA- and ligand 17-beta-estradiol-independent manner.TISSUE SPECIFICITY Expressed in the brain and the retina. Present in the developing brain, spinal cord and eye.DEVELOPMENTAL STAGE Expression peaks early in embryogenesis (day 13.5) and is undetectable 14 days after birth.DOMAIN The C-terminal domain is able to act as both DNA-binding domain and a transcriptional activator. The N-terminal domain is also required for transactivation activity on some target genes acting as a discrete activation domain. Neurite outgrowth and expression of genes required for synapse formation are primarily dependent on the C-terminal domain, however the N-terminal domain is required for maximal induction.SIMILARITY Belongs to the POU transcription factor family. Class-4 subfamily. UniProt Q01851 1 EQUAL 419 EQUAL Reactome Database ID Release 81 6804391 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804391 Reactome R-HSA-6804391 1 Reactome stable identifier. Use this 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-6804391.1 p-S15,S20-TP53 Tetramer:POU4F1 Reactome DB_ID: 6804394 1 1 Reactome Database ID Release 81 6804394 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804394 Reactome R-HSA-6804394 1 Reactome stable identifier. Use this 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-6804394.1 Reactome Database ID Release 81 6804402 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804402 Reactome R-HSA-6804402 2 Reactome stable identifier. Use this 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-6804402.2 15598651 Pubmed 2005 Brn-3a transcription factor blocks p53-mediated activation of proapoptotic target genes Noxa and Bax in vitro and in vivo to determine cell fate Hudson, Chantelle D Morris, Peter J Latchman, David S Budhram-Mahadeo, Vishwanie S J. Biol. Chem. 280:11851-8 10329733 Pubmed 1999 p53 suppresses the activation of the Bcl-2 promoter by the Brn-3a POU family transcription factor Budhram-Mahadeo, V Morris, P J Smith, M D Midgley, C A Boxer, L M Latchman, D S J. Biol. Chem. 274:15237-44 12203124 Pubmed 2002 The Brn-3a transcription factor inhibits the pro-apoptotic effect of p53 and enhances cell cycle arrest by differentially regulating the activity of the p53 target genes encoding Bax and p21(CIP1/Waf1) Budram-Mahadeo, Vishwanie Morris, Peter J Latchman, David S Oncogene 21:6123-31 LEFT-TO-RIGHT TP53 binds POU4F2 POU4F2 (BRN3B), similarly to POU4F1 (BRN3A), forms a complex with TP53 (p53). The interaction involves the POU domain of POU4F2 and the DNA binding domain of TP53. In contrast to POU4F1, binding of POU4F2 to TP53 enhances TP53-mediated transcriptional induction of pro-apoptotic targets such as BAX (Budhram-Mahadeo et al. 2006), NOXA and PUMA (Budhram-Mahadeo et al. 2014). The pro-apoptotic action of the complex of POU4F2 and TP53 may control the fate of cardiomyocytes in injured heart (Budhram-Mahadeo et al. 2014). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 BRN3B POU4F2 POU domain, class 4, transcription factor 2 Brain-specific homeobox/POU domain protein 3B Brn-3B Brain-3B Reactome DB_ID: 6804414 UniProt:Q12837 POU4F2 POU4F2 BRN3B FUNCTION Tissue-specific DNA-binding transcription factor involved in the development and differentiation of target cells (PubMed:19266028, PubMed:23805044). Functions either as activator or repressor modulating the rate of target gene transcription through RNA polymerase II enzyme in a promoter-dependent manner (PubMed:19266028, PubMed:23805044). Binds to the consensus octamer motif 5'-AT[A/T]A[T/A]T[A/T]A-3' of promoter of target genes. Plays a fundamental role in the gene regulatory network essential for retinal ganglion cell (RGC) differentiation. Binds to an octamer site to form a ternary complex with ISL1; cooperates positively with ISL1 and ISL2 to potentiate transcriptional activation of RGC target genes being involved in RGC fate commitment in the developing retina and RGC axon formation and pathfinding. Inhibits DLX1 and DLX2 transcriptional activities preventing DLX1- and DLX2-mediated ability to promote amacrine cell fate specification. In cooperation with TP53 potentiates transcriptional activation of BAX promoter activity increasing neuronal cell apoptosis. Negatively regulates BAX promoter activity in the absence of TP53. Acts as a transcriptional coactivator via its interaction with the transcription factor ESR1 by enhancing its effect on estrogen response element (ERE)-containing promoter. Antagonizes the transcriptional stimulatory activity of POU4F1 by preventing its binding to an octamer motif. Involved in TNFSF11-mediated terminal osteoclast differentiation (By similarity).SUBUNIT Interacts with POU4F1; this interaction inhibits both POU4F1 DNA-binding and transcriptional activities. Interacts (C-terminus) with ESR1 (via DNA-binding domain); this interaction increases the estrogen receptor ESR1 transcriptional activity in a DNA- and ligand 17-beta-estradiol-independent manner. Interacts (via C-terminus) with TP53 (via N-terminus). Interacts with DLX1 (via homeobox DNA-binding domain); this interaction suppresses DLX1-mediated transcriptional activity in postnatal retina enhancing retinal ganglion cell (RGC) differentiation. Interacts with DLX2 (via homeobox DNA-binding domain); this interaction enhances RGC differentiation. Interacts (via C-terminus) with ISL1 (via C-terminus). Interacts with ISL2. Interacts with LHX2.TISSUE SPECIFICITY Expressed in the brain (PubMed:7691107). Expressed in the ganglion cell layer of the retina (PubMed:7691107).DOMAIN The N-terminal transcriptional activation region is sufficient to induce transcriptional activity.DOMAIN The POU-specific domain and POU homeodomain regions are necessary for DNA-binding activity and transcriptional repression.DOMAIN The polyhistidine motif acts as a targeting signal to nuclear speckles.SIMILARITY Belongs to the POU transcription factor family. Class-4 subfamily. UniProt Q12837 1 EQUAL 409 EQUAL Reactome Database ID Release 81 6804414 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804414 Reactome R-HSA-6804414 1 Reactome stable identifier. Use this 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-6804414.1 p-S15,S20-TP53 Tetramer:POU4F2 Reactome DB_ID: 6804423 1 1 Reactome Database ID Release 81 6804423 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804423 Reactome R-HSA-6804423 1 Reactome stable identifier. Use this 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-6804423.1 Reactome Database ID Release 81 6804425 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804425 Reactome R-HSA-6804425 2 Reactome stable identifier. Use this 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-6804425.2 17145718 Pubmed 2006 Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression Budhram-Mahadeo, Vishwanie S Bowen, Samantha Lee, Sonia Perez-Sanchez, Christina Ensor, Elizabeth Morris, Peter J Latchman, David S Nucleic Acids Res. 34:6640-52 25356872 Pubmed 2014 Co-expression of POU4F2/Brn-3b with p53 may be important for controlling expression of pro-apoptotic genes in cardiomyocytes following ischaemic/hypoxic insults Budhram-Mahadeo, V Fujita, R Bitsi, S Sicard, P Heads, R Cell Death Dis 5:e1503 LEFT-TO-RIGHT TP53 binds PPP1R13L PPP1R13L encodes the inhibitory member of the ASPP family - iASPP. PPP1R13L binds TP53 (p53) and inhibits its pro-apoptotic transcriptional activity. PPP1R13L cooperates with RAS, adenovirus protein E1A and the human papillomavirus protein E7 in cell transformation (Bergamaschi et al. 2003, Wilson et al. 2014). The C-terminus of PPP1R13L consists of four ankyrin repeats and an SH3 domain that form a p53-binding site. PPP1R13L binds the DNA binding site of TP53 (Robinson et al. 2008). PPP1R13L also interacts with p53 family members TP63 (p63) and TP73 (p73) (Robinson et al. 2008) and inhibits their pro-apoptotic transcriptional activity (Cai et al. 2012). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 iASPP PPP1R13L RelA-associated inhibitor Inhibitor of ASPP protein Reactome DB_ID: 6799738 UniProt:Q8WUF5 PPP1R13L PPP1R13L IASPP NKIP1 PPP1R13BL RAI FUNCTION Regulator that plays a central role in regulation of apoptosis and transcription via its interaction with NF-kappa-B and p53/TP53 proteins. Blocks transcription of HIV-1 virus by inhibiting the action of both NF-kappa-B and SP1. Also inhibits p53/TP53 function, possibly by preventing the association between p53/TP53 and ASPP1 or ASPP2, and therefore suppressing the subsequent activation of apoptosis (PubMed:12524540).SUBUNIT Interacts with RELA NF-kappa-B subunit and with SP1 via its C-terminus part. Interacts (via SH3 domain and ANK repeats) with p53/TP53; the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with TP63 and TP73.TISSUE SPECIFICITY Highly expressed in heart, placenta and prostate. Weakly expressed in brain, liver, skeletal muscle, testis and peripheral blood leukocyte.DOMAIN The N-terminal region is required for cytoplasmic localization.DOMAIN The ANK repeats and the SH3 domain are required for specific interactions with p53/TP53.SIMILARITY Belongs to the iASPP family.CAUTION An alternative product iASPP(RAI) has been described (PubMed:15489900, PubMed:10336463). However, it is not detected in vivo and is most probably a cloning artifact (PubMed:15489900). UniProt Q8WUF5 1 EQUAL 828 EQUAL Reactome Database ID Release 81 6799738 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799738 Reactome R-HSA-6799738 1 Reactome stable identifier. Use this 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-6799738.1 Converted from EntitySet in Reactome p-S15,S20-TP53,TP63,TP73 Reactome DB_ID: 6798076 p63 tetramer TP63 Tetramer Reactome DB_ID: 5632381 TP63 Tumor protein 63 P63_HUMAN Reactome DB_ID: 2997585 UniProt:Q9H3D4 TP63 TP63 KET P63 P73H P73L TP73L FUNCTION 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. UniProt Q9H3D4 1 EQUAL 680 EQUAL Reactome Database ID Release 81 2997585 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997585 Reactome R-HSA-2997585 1 Reactome stable identifier. Use this 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-2997585.1 4 Reactome Database ID Release 81 5632381 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5632381 Reactome R-HSA-5632381 2 Reactome stable identifier. Use this 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-5632381.2 TP73 Tetramer Reactome DB_ID: 6798077 TP73 Tumor protein p73 Reactome DB_ID: 6798094 UniProt:O15350 TP73 TP73 P73 FUNCTION Participates in the apoptotic response to DNA damage. Isoforms containing the transactivation domain are pro-apoptotic, isoforms lacking the domain are anti-apoptotic and block the function of p53 and transactivating p73 isoforms. May be a tumor suppressor protein.SUBUNIT Found in a complex with p53/TP53 and CABLES1. The C-terminal oligomerization domain binds to the ABL1 tyrosine kinase SH3 domain. Interacts with HECW2. Isoform Beta interacts homotypically and with p53/TP53, whereas isoform Alpha does not. Isoform Gamma interacts homotypically and with all p73 isoforms. Isoform Delta interacts with isoform Gamma, isoform Alpha, and homotypically. Isoforms Alpha and Beta interact with HIPK2. Isoform Alpha interacts with RANBP9. Isoform Beta interacts with WWOX. Interacts (via SAM domain) with FBXO45 (via B30.2/SPRY domain). Interacts with YAP1 (phosphorylated form). Interacts with HCK (via SH3 domain); this inhibits TP73 activity and degradation.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein EBNA6; this interaction inhibits TP73-mediated apoptotic pathway.TISSUE SPECIFICITY Expressed in striatal neurons of patients with Huntington disease (at protein level). Brain, kidney, placenta, colon, heart, liver, spleen, skeletal muscle, prostate, thymus and pancreas. Highly expressed in fetal tissue.INDUCTION Not induced by DNA damage. Isoforms lacking the transactivation domain block gene induction.DOMAIN Possesses an acidic transactivation domain, a central DNA binding domain and a C-terminal oligomerization domain that binds to the ABL1 tyrosine kinase SH3 domain.DOMAIN The PPxY motif mediates interaction with WWOX.PTM Isoform alpha (but not isoform beta) is sumoylated on Lys-627, which potentiates proteasomal degradation but does not affect transcriptional activity. Phosphorylation by PLK1 and PLK3 inhibits the transcription regulator activity and pro-apoptotic function.PTM Higher levels of phosphorylation seen in the brain from patients with Huntington disease.PTM Polyubiquitinated by RCHY1/PIRH2; leading to its degradation by the proteasome.MISCELLANEOUS Maps to a chromosome region frequently mutated in diverse cell lines of human cancer. Appears not to be frequently mutated in human cancers, in contrast to p53/TP53. Hemizygosity is observed in neuroblastoma and oligodendroglioma.MISCELLANEOUS Activated and stabilized by interaction with RANBP9.SIMILARITY Belongs to the p53 family. UniProt O15350 1 EQUAL 636 EQUAL Reactome Database ID Release 81 6798094 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6798094 Reactome R-HSA-6798094 1 Reactome stable identifier. Use this 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-6798094.1 4 Reactome Database ID Release 81 6798077 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6798077 Reactome R-HSA-6798077 1 Reactome stable identifier. Use this 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-6798077.1 Reactome Database ID Release 81 6798076 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6798076 Reactome R-HSA-6798076 1 Reactome stable identifier. Use this 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-6798076.1 (p-S15,S20-TP53,TP63,TP73):iASSP (p-S15,S20-TP53,TP63,TP73):PPP1R13L Reactome DB_ID: 6799745 1 1 Reactome Database ID Release 81 6799745 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799745 Reactome R-HSA-6799745 1 Reactome stable identifier. Use this 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-6799745.1 Reactome Database ID Release 81 6799761 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799761 Reactome R-HSA-6799761 2 Reactome stable identifier. Use this 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-6799761.2 12524540 Pubmed 2003 iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human Bergamaschi, Daniele Samuels, Y O'Neil, Nigel J Trigiante, Giuseppe Crook, Tim Hsieh, Jung-Kuang O'Connor, Daniel J Zhong, Shan Campargue, Isabelle Tomlinson, Matthew L Kuwabara, Patricia E Lu, Xin Nat. Genet. 33:162-7 18275817 Pubmed 2008 Biochemical and structural studies of ASPP proteins reveal differential binding to p53, p63, and p73 Robinson, Ross Alexander Lu, Xin Jones, Edith Yvonne Siebold, Christian Structure 16:259-68 22538442 Pubmed 2012 iASPP inhibits p53-independent apoptosis by inhibiting transcriptional activity of p63/p73 on promoters of proapoptotic genes Cai, Yun Qiu, Shi Gao, Xing Gu, Shou-Zhi Liu, Ze-Jun Apoptosis 17:777-83 24714389 Pubmed 2014 Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is required for neuronal survival after axonal injury Wilson, Ariel M Chiodo, Vince A Boye, Sanford L Brecha, Nicholas C Hauswirth, William W Di Polo, Adriana PLoS ONE 9:e94175 LEFT-TO-RIGHT p53 family members bind ASPP1 or ASPP2 TP53 family members bind PPP1R13B or TP53BP2 TP53 (p53) forms a complex with PPP1R13B (ASPP1) or TP53BP2 (ASPP2). This interaction involves the DNA binding domain of TP53 and the C-terminus of ASSP proteins (Samuels-Lev et al. 2001, Patel et al. 2008). ASPP proteins can also form a complex with p53 family members TP63 (p63) and TP73 (p73) (Robinson et al. 2008, Patel et al. 2008). ASPP proteins enhance the binding of p53 family members to promoters of pro-apoptotic genes and promote their transcription, but do not affect the transcription of cell cycle regulators. ASPP proteins are frequently down-regulated in breast cancers that express wild-type TP53 (Samuels-Lev et al. 2001, Bergamaschi et al. 2004). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 Converted from EntitySet in Reactome ASPP1,ASPP2 PPP1R13B,TP53BP2 Reactome DB_ID: 6799786 ASPP1 PPP1R13B Apoptosis-stimulating of p53 protein 1 Protein phosphatase 1 regulatory subunit 13B Reactome DB_ID: 6799775 UniProt:Q96KQ4 PPP1R13B PPP1R13B ASPP1 KIAA0771 FUNCTION Regulator that plays a central role in regulation of apoptosis via its interaction with p53/TP53 (PubMed:11684014, PubMed:12524540). Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo.SUBUNIT Interacts with P53/TP53; the interaction promotes pro-apoptotic activity.TISSUE SPECIFICITY Reduced expression in breast carcinomas expressing a wild-type TP53 protein.DOMAIN The ankyrin repeats and the SH3 domain are required for specific interactions with TP53.MISCELLANEOUS In contrast to its official gene name, it is not a regulatory subunit of protein phosphatase 1. This name was given due to its similarity with a protein that binds to protein phosphatase 1.SIMILARITY Belongs to the ASPP family. UniProt Q96KQ4 1 EQUAL 1090 EQUAL Reactome Database ID Release 81 6799775 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799775 Reactome R-HSA-6799775 1 Reactome stable identifier. Use this 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-6799775.1 Bbp TP53BP2 Apoptosis-stimulating of p53 protein 2 ASPP2 Bcl2-binding protein 53BP2 p53-binding protein 2 Reactome DB_ID: 6799780 UniProt:Q13625 TP53BP2 TP53BP2 ASPP2 BBP FUNCTION Regulator that plays a central role in regulation of apoptosis and cell growth via its interactions with proteins such as TP53 (PubMed:12524540). Regulates TP53 by enhancing the DNA binding and transactivation function of TP53 on the promoters of proapoptotic genes in vivo. Inhibits the ability of NAE1 to conjugate NEDD8 to CUL1, and thereby decreases NAE1 ability to induce apoptosis. Impedes cell cycle progression at G2/M. Its apoptosis-stimulating activity is inhibited by its interaction with DDX42.SUBUNIT Interacts with P53/TP53; the interaction promotes pro-apoptotic activity (PubMed:11684014, PubMed:8016121, PubMed:12524540). Interacts with BCL2 (PubMed:8668206). Interacts with protein phosphatase 1. Interacts with RELA NF-kappa-B subunit. This interaction probably prevents the activation of apoptosis, possibly by preventing its interaction with TP53. Interacts with APC2 and NAE1. Interacts with DDX42 (via the C-terminus); the interaction is not inhibited by TP53BP2 ubiquitination and is independent of p53/TP53.TISSUE SPECIFICITY Widely expressed. Expressed in spleen, thymus, prostate, testis, ovary, small intestine, colon and peripheral blood leukocyte. Reduced expression in breast carcinomas expressing a wild-type TP53 protein. Overexpressed in lung cancer cell lines.INDUCTION Following DNA damage induced by UV irradiation. Down-regulated by wild-type, but not mutant, p53/TP53.DOMAIN The ankyrin repeats and the SH3 domain are required for a specific interactions with TP53.SIMILARITY Belongs to the ASPP family. UniProt Q13625 1 EQUAL 1128 EQUAL Reactome Database ID Release 81 6799780 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799780 Reactome R-HSA-6799780 1 Reactome stable identifier. Use this 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-6799780.1 Reactome Database ID Release 81 6799786 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799786 Reactome R-HSA-6799786 1 Reactome stable identifier. Use this 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-6799786.1 (p-S15,S20-TP53,TP63,TP73):(ASPP1,ASPP2) (p-S15,S20-TP53,TP63,TP73):(PPP1R13B,TP53BP2) Reactome DB_ID: 6799788 1 1 Reactome Database ID Release 81 6799788 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799788 Reactome R-HSA-6799788 1 Reactome stable identifier. Use this 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-6799788.1 Reactome Database ID Release 81 6799777 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6799777 Reactome R-HSA-6799777 2 Reactome stable identifier. Use this 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-6799777.2 18676979 Pubmed 2008 Molecular interactions of ASPP1 and ASPP2 with the p53 protein family and the apoptotic promoters PUMA and Bax Patel, Seema George, Roger Autore, Flavia Fraternali, Franca Ladbury, JE Nikolova, Penka V Nucleic Acids Res. 36:5139-51 14729977 Pubmed 2004 ASPP1 and ASPP2: common activators of p53 family members Bergamaschi, Daniele Samuels, Y Jin, B Duraisingham, Sai Crook, Tim Lu, Xin Mol. Cell. Biol. 24:1341-50 11684014 Pubmed 2001 ASPP proteins specifically stimulate the apoptotic function of p53 Samuels-Lev, Y O'Connor, D J Bergamaschi, D Trigiante, G Hsieh, J K Zhong, S Campargue, I Naumovski, L Crook, T Lu, X Mol. Cell 8:781-94 LEFT-TO-RIGHT BANP binds TP53 BANP (SMAR1) binds TP53 (p53) and is implicated in both positive (Kaul et al. 2003, Jalota et al. 2005) and negative regulation of TP53 transcriptional activity (Pavithra et al. 2009, Sinha et al. 2010). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 BANP Protein BANP BEN domain-containing protein 1 Btg3-associated nuclear protein Scaffold/matrix-associated region-1-binding protein BEND1 SMAR1 Reactome DB_ID: 3221973 UniProt:Q8N9N5 BANP BANP BEND1 SMAR1 FUNCTION Controls V(D)J recombination during T-cell development by repressing T-cell receptor (TCR) beta enhancer function. Binds to scaffold/matrix attachment region beta (S/MARbeta), an ATC-rich DNA sequence located upstream of the TCR beta enhancer. Represses cyclin D1 transcription by recruiting HDAC1 to its promoter, thereby diminishing H3K9ac, H3S10ph and H4K8ac levels. Promotes TP53 activation, which causes cell cycle arrest (By similarity).SUBUNIT Interacts with TP53 (By similarity). Interacts with CUX1/CDP (By similarity). Interacts with HDAC1 (PubMed:16166625). Part of a corepressor complex containing BANP, HDAC1, SIN3A, SIN3B, RBL1 and RBL2 (PubMed:16166625).TISSUE SPECIFICITY Down-regulated in breast cancer cell lines.SIMILARITY Belongs to the BANP/SMAR1 family. UniProt Q8N9N5 1 EQUAL 519 EQUAL Reactome Database ID Release 81 3221973 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3221973 Reactome R-HSA-3221973 1 Reactome stable identifier. Use this 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-3221973.1 TP53 Tetramer Reactome DB_ID: 3209194 TP53 p53 protein P53_HUMAN Cellular tumor antigen p53 Tumor suppressor p53 Phosphoprotein p53 Antigen NY-CO-13 Reactome DB_ID: 69488 1 EQUAL 393 EQUAL Reactome Database ID Release 81 69488 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69488 Reactome R-HSA-69488 1 Reactome stable identifier. Use this 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-69488.1 4 Reactome Database ID Release 81 3209194 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3209194 Reactome R-HSA-3209194 1 Reactome stable identifier. Use this 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-3209194.1 TP53:BANP Reactome DB_ID: 3221977 1 1 Reactome Database ID Release 81 3221977 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3221977 Reactome R-HSA-3221977 1 Reactome stable identifier. Use this 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-3221977.1 Reactome Database ID Release 81 3221982 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3221982 Reactome R-HSA-3221982 2 Reactome stable identifier. Use this 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-3221982.2 15701641 Pubmed 2005 Tumor suppressor SMAR1 activates and stabilizes p53 through its arginine-serine-rich motif Jalota, Archana Singh, Kamini Pavithra, Lakshminarasimhan Kaul-Ghanekar, Ruchika Jameel, Shahid Chattopadhyay, Samit J. Biol. Chem. 280:16019-29 19303885 Pubmed 2009 SMAR1 forms a ternary complex with p53-MDM2 and negatively regulates p53-mediated transcription Pavithra, Lakshminarasimhan Mukherjee, Srijata Sreenath, Kadreppa Kar, Sanchari Sakaguchi, Kazuyasu Roy, Siddhartha Chattopadhyay, Samit J. Mol. Biol. 388:691-702 20075864 Pubmed 2010 Coordinated regulation of p53 apoptotic targets BAX and PUMA by SMAR1 through an identical MAR element Sinha, Surajit Malonia, Sunil Kumar Mittal, Smriti P K Singh, Kamini Kadreppa, Sreenath Kamat, Rohan Mukhopadhyaya, Robin Pal, Jayanta K Chattopadhyay, Samit EMBO J. 29:830-42 12494467 Pubmed 2003 Direct interaction with and activation of p53 by SMAR1 retards cell-cycle progression at G2/M phase and delays tumor growth in mice Kaul, Ruchika Mukherjee, Sujoy Ahmed, Farid Bhat, Manoj Kumar Chhipa, Rishiraj Galande, Sanjeev Chattopadhyay, Samit Int. J. Cancer 103:606-15 LEFT-TO-RIGHT PHF20 binds TP53 dimethylated on K370 and K382 PHF20 binds TP53 (p53) dimethylated at lysine residues K370 and K382 by unidentified protein lysine methyltransferase(s). PHF20 binding interferes with MDM2 binding to TP53, thus resulting in TP53 stabilization (Cui et al. 2012). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 NZF PHF20 PHD finger protein 20 Glioma-expressed antigen 2 Hepatocellular carcinoma-associated antigen 58 Novel zinc finger protein Transcription factor TZP C20orf104 GLEA2 HCA58 TZP Reactome DB_ID: 3222239 UniProt:Q9BVI0 PHF20 PHF20 C20orf104 GLEA2 HCA58 NZF TZP FUNCTION Methyllysine-binding protein, component of the MOF histone acetyltransferase protein complex. Not required for maintaining the global histone H4 'Lys-16' acetylation (H4K16ac) levels or locus specific histone acetylation, but instead works downstream in transcriptional regulation of MOF target genes (By similarity). As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. Contributes to methyllysine-dependent p53/TP53 stabilization and up-regulation after DNA damage.SUBUNIT Homodimer; disulfide-linked. Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, KAT8/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10. Component of the NSL complex at least composed of MOF/KAT8, KANSL1, KANSL2, KANSL3, MCRS1, PHF20, OGT1/OGT, WDR5 and HCFC1.TISSUE SPECIFICITY Expressed in heart, kidney, liver, lung, pancreas, placenta, spleen and testis. Not expressed in brain, skeletal muscle, colon, ovary, prostate, small intestine and thymus. Expressed in colon and ovary cancer cell lines while it is not expressed in the respective normal tissues.DOMAIN The Tudor domain 2 mediates reading of dimethyl-lysine residues.DOMAIN The Tudor domain 1 doesn't bind dimethyl-lysine residues, due to an atypical and occluded aromatic cage.MISCELLANEOUS Antibodies against PHF20 are present in sera from patients with hepatocellular carcinoma, glioblastoma and childhood medulloblastula. UniProt Q9BVI0 1 EQUAL 1012 EQUAL Reactome Database ID Release 81 3222239 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222239 Reactome R-HSA-3222239 1 Reactome stable identifier. Use this 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-3222239.1 Me2-K370,K382-TP53 Tetramer Reactome DB_ID: 3222245 Me2K-370,382-TP53 Me2-K370,K382-TP53 Reactome DB_ID: 3222242 370 EQUAL N6,N6-dimethyl-L-lysine MOD MOD:00084 382 EQUAL 1 EQUAL 393 EQUAL Reactome Database ID Release 81 3222242 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222242 Reactome R-HSA-3222242 1 Reactome stable identifier. Use this 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-3222242.1 4 Reactome Database ID Release 81 3222245 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222245 Reactome R-HSA-3222245 1 Reactome stable identifier. Use this 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-3222245.1 PHF20:Me2-K370,K382-TP53 Tetramer Reactome DB_ID: 3222249 1 1 Reactome Database ID Release 81 3222249 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222249 Reactome R-HSA-3222249 1 Reactome stable identifier. Use this 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-3222249.1 Reactome Database ID Release 81 3222259 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3222259 Reactome R-HSA-3222259 1 Reactome stable identifier. Use this 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-3222259.1 22864287 Pubmed 2012 PHF20 is an effector protein of p53 double lysine methylation that stabilizes and activates p53 Cui, Gaofeng Park, Sungman Badeaux, Aimee I Kim, Donghwa Lee, Joseph Thompson, James R Yan, Fei Kaneko, Satoshi Yuan, Zengqiang Botuyan, Maria Victoria Bedford, Mark T Cheng, Jin Q Mer, Georges Nat. Struct. Mol. Biol. 19:916-24 LEFT-TO-RIGHT 2.7.11.1 AKT phosphorylates PHF20 AKT phosphorylates PHF20 on serine residue S291 (Park et al. 2012, Li et al. 2013), triggering PHF20 translocation to the cytosol (Park et al. 2012). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 81 29358 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29358 Reactome R-ALL-29358 3 Reactome stable identifier. Use this 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-29358.3 COMPOUND C00002 additional information MI MI:0361 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 81 113582 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=113582 Reactome R-ALL-113582 3 Reactome stable identifier. Use this 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-113582.3 COMPOUND C00008 p-S291-PHF20 Reactome DB_ID: 6805776 291 EQUAL 1 EQUAL 1012 EQUAL Reactome Database ID Release 81 6805776 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805776 Reactome R-HSA-6805776 1 Reactome stable identifier. Use this 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-6805776.1 ACTIVATION Converted from EntitySet in Reactome Active AKT p-T,p-S-AKT p-T308,S473-AKT1,(p-T309,S474-AKT2,p-T305,S472-AKT3) Reactome DB_ID: 202072 PKB p-T308,S473-AKT1 p-S473,T308-AKT1 Phospho-AKT1 (T308, S473) RAC-alpha serine/threonine kinase RAC-PK-alpha Protein kinase B C-AKT Reactome DB_ID: 198357 UniProt:P31749 AKT1 AKT1 PKB RAC FUNCTION 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). Also acts as an activator of TMEM175 potassium channel activity in response to growth factors: forms the lysoK(GF) complex together with TMEM175 and acts by promoting TMEM175 channel activation, independently of its protein kinase activity (PubMed:32228865).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). Interacts with TMEM175; leading to formation of the lysoK(GF) complex (PubMed:32228865). Acts as a negative regulator of the cGAS-STING pathway by mediating phosphorylation of CGAS during mitosis, leading to its inhibition (PubMed:26440888).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; undergoes both 'Lys-48'- and 'Lys-63'-linked polyubiquitination. TRAF6-induced 'Lys-63'-linked AKT1 ubiquitination is critical for phosphorylation and activation (PubMed:19713527). When ubiquitinated, it translocates to the plasma membrane, where it becomes phosphorylated (PubMed:20059950). When fully phosphorylated and translocated into the nucleus, undergoes 'Lys-48'-polyubiquitination catalyzed by TTC3, leading to its degradation by the proteasome (PubMed:20059950). Also ubiquitinated by TRIM13 leading to its proteasomal degradation (PubMed:21333377). Phosphorylated, undergoes 'Lys-48'-linked polyubiquitination preferentially at Lys-284 catalyzed by MUL1, leading to its proteasomal degradation (PubMed:22410793). Ubiquitinated via 'Lys-48'-linked polyubiquitination by ZNRF1, leading to its degradation by the proteasome (By similarity).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.PTM Cleavage by caspase-3/CASP3 (By similarity). Cleaved at the caspase-3 consensus site Asp-462 during apoptosis, resulting in down-regulation of the AKT signaling pathway and decreased cell survival (PubMed:23152800).DISEASE Genetic variations in AKT1 may play a role in susceptibility to ovarian cancer.MISCELLANEOUS (2S)-2-(4-chlorobenzyl)-3-oxo-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl]propan-1-amine corresponds to compound 44.MISCELLANEOUS 5-(5-chloro-1H-pyrrolo[2,3-d]pyrimidin-4-yl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine corresponds to compound 8b.SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. RAC subfamily.CAUTION PUBMED:19940129 has been retracted because the same data were used to represent different experimental conditions.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. UniProt P31749 308 EQUAL O-phospho-L-threonine MOD MOD:00047 473 EQUAL 1 EQUAL 480 EQUAL Reactome Database ID Release 81 198357 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=198357 Reactome R-HSA-198357 1 Reactome stable identifier. Use this 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-198357.1 PKB beta p-T309,S474-AKT2 Phospho-AKT2 (T309, S474) RAC-beta serine/threonine protein kinase RAC-PK-beta Protein kinase Akt-2 Protein kinase B, beta Reactome DB_ID: 202087 UniProt:P31751 AKT2 AKT2 FUNCTION 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.MISCELLANEOUS 4-[2-(4-amino-2,5-dihydro-1,2,5-oxadiazol-3-yl)-6-{[(1S)-3-amino-1-phenylpropyl]oxy}-1-ethyl-1H-imidazo[4,5-c]pyridin-4-yl]-2-methylbut-3-yn-2-ol corresponds to compound 32.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. UniProt P31751 309 EQUAL 474 EQUAL 1 EQUAL 481 EQUAL Reactome Database ID Release 81 202087 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202087 Reactome R-HSA-202087 1 Reactome stable identifier. Use this 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-202087.1 AKT3 p-T305,S472-AKT3 RAC-gamma serine/threonine-protein kinase ecNumber2.7.11.1/ecNumber AKT3_HUMAN Reactome DB_ID: 3009365 UniProt:Q9Y243 AKT3 AKT3 PKBG FUNCTION 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. UniProt Q9Y243 305 EQUAL 472 EQUAL 1 EQUAL 479 EQUAL Reactome Database ID Release 81 3009365 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3009365 Reactome R-HSA-3009365 1 Reactome stable identifier. Use this 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-3009365.1 Reactome Database ID Release 81 202072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=202072 Reactome R-HSA-202072 4 Reactome stable identifier. Use this 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-202072.4 GENE ONTOLOGY GO:0004674 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 199274 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=199274 Reactome Database ID Release 81 6805785 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805785 Reactome R-HSA-6805785 2 Reactome stable identifier. Use this 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-6805785.2 22975685 Pubmed 2013 PKB-mediated PHF20 phosphorylation on Ser291 is required for p53 function in DNA damage Li, Yuwen Park, Jisoo Piao, Longzhen Kong, Gyeyeong Kim, Yongbaek Park, Kyeong Ah Zhang, Tiejun Hong, Janghee Hur, Gang Min Seok, Jeong Ho Choi, Seung-Won Yoo, Byong Chul Hemmings, BA Brazil, Derek P Kim, Seon-Hwan Park, Jongsun Cell. Signal. 25:74-84 22334668 Pubmed 2012 Identification of Akt interaction protein PHF20/TZP that transcriptionally regulates p53 Park, Sungman Kim, Donghwa Dan, Han C Chen, Huihua Testa, Joseph R Cheng, Jin Q J. Biol. Chem. 287:11151-63 LEFT-TO-RIGHT p-S291-PHF20 translocates to cytosol PHF20 phosphorylated at serine S291 by AKT (Park et al. 2012, Li et al. 2013) translocates to the cytosol (Park et al. 2012). AKT thus prevents PHF20-mediated stimulation of TP53 (p53) activity (Park et al. 2012, Li et al. 2013). Authored: Orlic-Milacic, Marija, 2015-10-14 Reviewed: Zaccara, Sara, 2016-02-04 Reviewed: Inga, Alberto, 2016-02-04 Edited: Orlic-Milacic, Marija, 2015-10-14 p-S291-PHF20 Reactome DB_ID: 6805794 cytosol GENE ONTOLOGY GO:0005829 1 EQUAL 1012 EQUAL Reactome Database ID Release 81 6805794 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805794 Reactome R-HSA-6805794 1 Reactome stable identifier. Use this 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-6805794.1 Reactome Database ID Release 81 6805792 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805792 Reactome R-HSA-6805792 1 Reactome stable identifier. Use this 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-6805792.1 Reactome Database ID Release 81 6804759 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6804759 Reactome R-HSA-6804759 2 Reactome stable identifier. Use this 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-6804759.2 20673990 Pubmed 2010 A large intergenic noncoding RNA induced by p53 mediates global gene repression in the p53 response Huarte, Maite Guttman, Mitchell Feldser, David Garber, Manuel Koziol, Magdalena J Kenzelmann-Broz, Daniela Khalil, Ahmad M Zuk, Or Amit, Ido Rabani, Michal Attardi, Laura D Regev, A Lander, Eric S Jacks, Tyler Rinn, John L Cell 142:409-19 20691894 Pubmed 2010 Noncoding RNAs: the missing "linc" in p53-mediated repression Barsotti, Anthony M Prives, Carol Cell 142:358-60 20679336 Pubmed 2010 Transcriptional regulation by p53 Beckerman, Rachel Prives, Carol Cold Spring Harb Perspect Biol 2:a000935 18719709 Pubmed 2008 A complex barcode underlies the heterogeneous response of p53 to stress Murray-Zmijewski, Fiona Slee, Elizabeth A Lu, Xin Nat. Rev. Mol. Cell Biol. 9:702-12 18278067 Pubmed 2008 Mechanisms of regulatory diversity within the p53 transcriptional network Espinosa, J M Oncogene 27:4013-23 17719542 Pubmed 2007 hCAS/CSE1L associates with chromatin and regulates expression of select p53 target genes Tanaka, Tomoaki Ohkubo, Shuichi Tatsuno, Ichiro Prives, Carol Cell 130:638-50 15186775 Pubmed 2004 Ordered cooperative functions of PRMT1, p300, and CARM1 in transcriptional activation by p53 An, Woojin Kim, Jaehoon Roeder, Robert G Cell 117:735-48 GENE ONTOLOGY GO:1901796 gene ontology term for cellular process MI MI:0359