BioPAX pathway converted from "Regulation of gene expression in beta cells" in the Reactome database. Regulation of gene expression in beta cells Two transcription factors, PDX1 and HNF1A, play key roles in maintaining the gene expression pattern characteristic of mature beta cells in the endocrine pancreas. Targets of these regulatory molecules include genes encoding insulin, the GLUT2 glucose transporter, the liver- (and pancreas) specific form of pyruvate kinase and other transcription factors including HNF4A, HNF4G, and FOXA3. PDX1 expression in turn is controlled by the activities of MAFA, FOXA2, and PAX6, and negatively regulated via AKT (Chakrabarti and Mirmira 2003; Servitja and Ferrer 2004). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 AKT-mediated inactivation of FOXO1A The unphosphorylated form of FOXO1A shuttles between the nucleus and cytoplasm, maintaining a substantial concentration of this protein in the nucleoplasm, where it functions as a transcription factor. Phosphorylation of the protein, catalyzed by activated AKT, causes its exclusion from the nucleus (Zhang et al. 2002). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 LEFT-TO-RIGHT 2.7.11.1 AKT phosphorylates FOXO1A One or more of the isoforms of AKT catalyzes the phosphorylation of FOXO1A protein at three sites, threonine-24, serine-256, and serine-319 (Zhang et al. 2002, 2006). This reaction occurs in the nucleoplasm, and thus is dependent on the phosphorylation and nuclear import of AKT in response to upstream regulatory factors (Burgering and Kops 2002). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 nucleoplasm GENE ONTOLOGY GO:0005654 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 Reactome http://www.reactome.org COMPOUND C00002 additional information MI MI:0361 3 FOXO1 Forkhead box protein O1A FOXO1_HUMAN FOXO1A Reactome DB_ID: 199300 UniProt:Q12778 FOXO1 FOXO1 FKHR FOXO1A FUNCTION Transcription factor that is the main target of insulin signaling and regulates metabolic homeostasis in response to oxidative stress (PubMed:10358076, PubMed:12228231, PubMed:15220471, PubMed:15890677, PubMed:18356527, PubMed:19221179, PubMed:20543840, PubMed:21245099). Binds to the insulin response element (IRE) with consensus sequence 5'-TT[G/A]TTTTG-3' and the related Daf-16 family binding element (DBE) with consensus sequence 5'-TT[G/A]TTTAC-3' (PubMed:10358076). Activity suppressed by insulin (PubMed:10358076). Main regulator of redox balance and osteoblast numbers and controls bone mass (By similarity). Orchestrates the endocrine function of the skeleton in regulating glucose metabolism (By similarity). Also acts as a key regulator of chondrogenic commitment of skeletal progenitor cells in response to lipid availability: when lipids levels are low, translocates to the nucleus and promotes expression of SOX9, which induces chondrogenic commitment and suppresses fatty acid oxidation (By similarity). Acts synergistically with ATF4 to suppress osteocalcin/BGLAP activity, increasing glucose levels and triggering glucose intolerance and insulin insensitivity (By similarity). Also suppresses the transcriptional activity of RUNX2, an upstream activator of osteocalcin/BGLAP (By similarity). In hepatocytes, promotes gluconeogenesis by acting together with PPARGC1A and CEBPA to activate the expression of genes such as IGFBP1, G6PC1 and PCK1 (By similarity). Important regulator of cell death acting downstream of CDK1, PKB/AKT1 and STK4/MST1 (PubMed:18356527, PubMed:19221179). Promotes neural cell death (PubMed:18356527). Mediates insulin action on adipose tissue (By similarity). Regulates the expression of adipogenic genes such as PPARG during preadipocyte differentiation and, adipocyte size and adipose tissue-specific gene expression in response to excessive calorie intake (By similarity). Regulates the transcriptional activity of GADD45A and repair of nitric oxide-damaged DNA in beta-cells (By similarity). Required for the autophagic cell death induction in response to starvation or oxidative stress in a transcription-independent manner (PubMed:20543840). Mediates the function of MLIP in cardiomyocytes hypertrophy and cardiac remodeling (By similarity). Regulates endothelial cell (EC) viability and apoptosis in a PPIA/CYPA-dependent manner via transcription of CCL2 and BCL2L11 which are involved in EC chemotaxis and apoptosis (PubMed:31063815).SUBUNIT Interacts with LRPPRC. Interacts with RUNX2; the interaction inhibits RUNX2 transcriptional activity and mediates the IGF1/insulin-dependent BGLAP expression in osteoblasts Interacts with PPP2R1A; the interaction regulates the dephosphorylation of FOXO1 at Thr-24 and Ser-256 leading to its nuclear import. Interacts (acetylated form) with PPARG. Interacts with XBP1 isoform 2; this interaction is direct and leads to FOXO1 ubiquitination and degradation via the proteasome pathway (By similarity). Interacts with NLK. Interacts with SIRT1; the interaction results in the deacetylation of FOXO1 leading to activation of FOXO1-mediated transcription of genes involved in DNA repair and stress resistance. Binds to CDK1. Interacts with the 14-3-3 proteins, YWHAG and YWHAZ; the interactions require insulin-stimulated phosphorylation on Thr-24, promote nuclear exit and loss of transcriptional activity. Interacts with SKP2; the interaction ubiquitinates FOXO1 leading to its proteosomal degradation. The interaction requires the presence of KRIT1. Interacts (via the C-terminal half) with ATF4 (via its DNA-binding domain); the interaction occurs in osteoblasts, regulates glucose homeostasis via suppression of beta-cell proliferation and subsequent decrease in insulin production. Interacts with PRMT1; the interaction methylates FOXO1, prevents PKB/AKT1 phosphorylation and retains FOXO1 in the nucleus. Interacts with EP300 and CREBBP; the interactions acetylate FOXO1. Interacts with SIRT2; the interaction is disrupted in response to oxidative stress or serum deprivation, leading to increased level of acetylated FOXO1, which promotes stress-induced autophagy by stimulating E1-like activating enzyme ATG7. Interacts (acetylated form) with ATG7; the interaction is increased in response to oxidative stress or serum deprivation and promotes the autophagic process leading to cell death. Interacts (via the Fork-head domain) with CEBPA; the interaction increases when FOXO1 is deacetylated. Interacts with WDFY2. Forms a complex with WDFY2 and AKT1 (By similarity). Interacts with CRY1 (By similarity). Interacts with PPIA/CYPA; the interaction promotes FOXO1 dephosphorylation, nuclear accumulation and transcriptional activity (PubMed:31063815).TISSUE SPECIFICITY Ubiquitous.INDUCTION Expression is regulated by KRIT1. Levels of expression also regulated by FOXC1 which binds to a conserved element in the FOXO1 promoter.PTM Phosphorylation by NLK promotes nuclear export and inhibits the transcriptional activity. In response to growth factors, phosphorylation on Thr-24, Ser-256 and Ser-322 by PKB/AKT1 promotes nuclear export and inactivation of transactivational activity. Phosphorylation on Thr-24 is required for binding 14-3-3 proteins. Phosphorylation of Ser-256 decreases DNA-binding activity and promotes the phosphorylation of Thr-24 and Ser-319, permitting phosphorylation of Ser-322 and Ser-325, probably by CDK1, leading to nuclear exclusion and loss of function. Stress signals, such as response to oxygen or nitric oxide, attenuate the PKB/AKT1-mediated phosphorylation leading to nuclear retention. Phosphorylation of Ser-329 is independent of IGF1 and leads to reduced function. Dephosphorylated on Thr-24 and Ser-256 by PP2A in beta-cells under oxidative stress leading to nuclear retention (By similarity). Phosphorylation of Ser-249 by CDK1 disrupts binding of 14-3-3 proteins leading to nuclear accumulation and has no effect on DNA-binding nor transcriptional activity. Phosphorylation by STK4/MST1 on Ser-212, upon oxidative stress, inhibits binding to 14-3-3 proteins and nuclear export. PPIA/CYPA promotes its dephosphorylation on Ser-256 (PubMed:31063815).PTM Acetylated. Acetylation at Lys-262, Lys-265 and Lys-274 are necessary for autophagic cell death induction. Deacetylated by SIRT2 in response to oxidative stress or serum deprivation, thereby negatively regulating FOXO1-mediated autophagic cell death.PTM Ubiquitinated by SKP2. Ubiquitination leads to proteasomal degradation.PTM Methylation inhibits AKT1-mediated phosphorylation at Ser-256 and is increased by oxidative stress.PTM Once in the nucleus, acetylated by CREBBP/EP300. Acetylation diminishes the interaction with target DNA and attenuates the transcriptional activity. It increases the phosphorylation at Ser-256. Deacetylation by SIRT1 results in reactivation of the transcriptional activity. Oxidative stress by hydrogen peroxide treatment appears to promote deacetylation and uncoupling of insulin-induced phosphorylation. By contrast, resveratrol acts independently of acetylation. Homo sapiens NCBI Taxonomy 9606 UniProt Q12778 1 EQUAL 655 EQUAL Reactome Database ID Release 81 199300 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=199300 Reactome R-HSA-199300 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-199300.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5'-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 3 FOXO1A p-T24,S256,S319-FOXO1 Phospho-Forkhead box protein O1A (T24, S256, S319) FOXO1_HUMAN Reactome DB_ID: 199306 24 EQUAL O-phospho-L-threonine MOD MOD:00047 256 EQUAL O-phospho-L-serine MOD MOD:00046 319 EQUAL 1 EQUAL 655 EQUAL Reactome Database ID Release 81 199306 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=199306 Reactome R-HSA-199306 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-199306.1 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 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 211164 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=211164 Reactome R-HSA-211164 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-211164.1 12228231 Pubmed 2002 Phosphorylation of serine 256 suppresses transactivation by FKHR (FOXO1) by multiple mechanisms. Direct and indirect effects on nuclear/cytoplasmic shuttling and DNA binding Zhang, X Gan, L Pan, H Guo, S He, X Olson, ST Mesecar, A Adam, S Unterman, TG J Biol Chem 277:45276-84 16540465 Pubmed 2006 Kinetic mechanism of AKT/PKB enzyme family Zhang, X Zhang, S Yamane, H Wahl, R Ali, A Lofgren, JA Kendall, RL J Biol Chem 281:13949-56 12114024 Pubmed 2002 Cell cycle and death control: long live Forkheads Burgering, BM Kops, GJ Trends Biochem Sci 27:352-60 LEFT-TO-RIGHT Phosphorylated FOXO1A is excluded from the nucleus Phosphorylated FOXO1A is transported from the nucleoplasm to the cytosol (Zhang et al. 2002). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 FOXO1A p-T24,S256,S319-FOXO1 Phospho-Forkhead box protein O1A (T24, S256, S319) FOXO1_HUMAN Reactome DB_ID: 211158 cytosol GENE ONTOLOGY GO:0005829 1 EQUAL 655 EQUAL Reactome Database ID Release 81 211158 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=211158 Reactome R-HSA-211158 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-211158.1 Reactome Database ID Release 81 211178 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=211178 Reactome R-HSA-211178 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-211178.1 Reactome Database ID Release 81 211163 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=211163 Reactome R-HSA-211163 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-211163.2 GENE ONTOLOGY GO:2000074 gene ontology term for cellular process MI MI:0359 LEFT-TO-RIGHT FOXOA2-, MAFA-, and PAX6-dependent synthesis of PDX1 protein The PDX1 (IPF1) gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. PDX1 transcription is positively regulated by the activities of the FOXA2, MAFA, and PAX6 transcription factors. It is negatively regulated by FOXO1A, so events that deplete the nucleoplasmic pool of FOXO1A increase expression of PDX1. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 PDX1 gene Reactome DB_ID: 9606088 ENSEMBL:ENSG00000139515 PDX1 PDX1 IPF1 STF1 ENSEMBL ENSG00000139515 Reactome Database ID Release 81 9606088 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=9606088 Reactome R-HSA-9606088 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-9606088.1 PDX1 IPF1 Reactome DB_ID: 211179 UniProt:P52945 PDX1 PDX1 IPF1 STF1 FUNCTION Activates insulin, somatostatin, glucokinase, islet amyloid polypeptide and glucose transporter type 2 gene transcription. Particularly involved in glucose-dependent regulation of insulin gene transcription. As part of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells is involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element. Binds preferentially the DNA motif 5'-[CT]TAAT[TG]-3'. During development, specifies the early pancreatic epithelium, permitting its proliferation, branching and subsequent differentiation. At adult stage, required for maintaining the hormone-producing phenotype of the beta-cell.SUBUNIT Interacts with the basic helix-loop-helix domains of TCF3(E47) and NEUROD1 and with HMG-I(Y). Interacts with SPOP (By similarity). Interacts with the methyltransferase SETD7. Part of a PDX1:PBX1b:MEIS2b complex.TISSUE SPECIFICITY Duodenum and pancreas (Langerhans islet beta cells and small subsets of endocrine non-beta-cells, at low levels in acinar cells).DOMAIN The Antp-type hexapeptide mediates heterodimerization with PBX on a regulatory element of the somatostatin promoter.DOMAIN The homeodomain, which contains the nuclear localization signal, not only mediates DNA-binding, but also acts as a protein-protein interaction domain for TCF3(E47), NEUROD1 and HMG-I(Y).PTM Phosphorylated by the SAPK2 pathway at high intracellular glucose concentration. Phosphorylated by HIPK2 on Ser-268 upon glucose accumulation. This phosphorylation mediates subnuclear localization shifting. Phosphorylation by PASK may lead to translocation into the cytosol (By similarity).MISCELLANEOUS According to PubMed:16141209, it may be methylated by SETD7 in vitro. However, the relevance of methylation is unsure in vivo.SIMILARITY Belongs to the Antp homeobox family. IPF1/XlHbox-8 subfamily. UniProt P52945 1 EQUAL 283 EQUAL Reactome Database ID Release 81 211179 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=211179 Reactome R-HSA-211179 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-211179.1 Reactome Database ID Release 81 211272 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=211272 Reactome R-HSA-211272 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-211272.3 INHIBITION Reactome Database ID Release 81 211284 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=211284 Reactome R-HSA-211284 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-211284.1 ACTIVATION Reactome Database ID Release 81 211575 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=211575 Reactome R-HSA-211575 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-211575.1 PAX6 Paired box protein Pax-6 PAX6_HUMAN Reactome DB_ID: 3009044 UniProt:P26367 PAX6 PAX6 AN2 FUNCTION Transcription factor with important functions in the development of the eye, nose, central nervous system and pancreas. Required for the differentiation of pancreatic islet alpha cells (By similarity). Competes with PAX4 in binding to a common element in the glucagon, insulin and somatostatin promoters. Regulates specification of the ventral neuron subtypes by establishing the correct progenitor domains (By similarity). Acts as a transcriptional repressor of NFATC1-mediated gene expression (By similarity).SUBUNIT Interacts with MAF and MAFB (By similarity). Interacts with TRIM11; this interaction leads to ubiquitination and proteasomal degradation, as well as inhibition of transactivation, possibly in part by preventing PAX6 binding to consensus DNA sequences (By similarity). Interacts with TLE6/GRG6 (By similarity).DEVELOPMENTAL STAGE Expressed in the developing eye and brain. Expression in the retina peaks at fetal days 51-60. At 6-week old, in the retina, is predominantly detected in the neural layer (at protein level). At 8- and 10-week old, in the retina, the expression is strongest in the inner and middle layer of the neural part (at protein level).PTM Ubiquitinated by TRIM11, leading to ubiquitination and proteasomal degradation.SIMILARITY Belongs to the paired homeobox family. UniProt P26367 1 EQUAL 422 EQUAL Reactome Database ID Release 81 3009044 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=3009044 Reactome R-HSA-3009044 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-3009044.1 ACTIVATION Reactome Database ID Release 81 211282 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=211282 Reactome R-HSA-211282 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-211282.1 MAFA MafA Reactome DB_ID: 211283 UniProt:Q8NHW3 MAFA MAFA FUNCTION Transcription factor that activates insulin gene expression (PubMed:15993959, PubMed:12011435). Acts synergistically with NEUROD1/BETA2 and PDX1 (PubMed:15993959). Binds the insulin enhancer C1/RIPE3b element (PubMed:12011435). Binds to consensus TRE-type MARE 5'-TGCTGACTCAGCA-3' DNA sequence (PubMed:23148532, PubMed:29339498).SUBUNIT Forms homodimers or heterodimers (PubMed:12011435, PubMed:23148532). Monomers and dimers are able to bind DNA, but the off-rate is faster for monomers (PubMed:23148532). Interacts with NEUROD1 and PDX1 (By similarity). May interact with MAFB, FOS, JUN and PCAF (By similarity).TISSUE SPECIFICITY Expressed in the islets of Langerhans (at protein level).PTM Ubiquitinated, leading to its degradation by the proteasome.PTM Phosphorylated at tyrosines.SIMILARITY Belongs to the bZIP family. Maf subfamily. UniProt Q8NHW3 1 EQUAL 353 EQUAL Reactome Database ID Release 81 211283 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=211283 Reactome R-HSA-211283 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-211283.1 ACTIVATION Reactome Database ID Release 81 211277 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=211277 Reactome R-HSA-211277 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-211277.1 FOXA2 FOXOA2 Reactome DB_ID: 211275 UniProt:Q9Y261 FOXA2 FOXA2 HNF3B TCF3B FUNCTION Transcription factor that is involved in embryonic development, establishment of tissue-specific gene expression and regulation of gene expression in differentiated tissues. Is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites. Binds DNA with the consensus sequence 5'-[AC]A[AT]T[AG]TT[GT][AG][CT]T[CT]-3' (By similarity). In embryonic development is required for notochord formation. Involved in the development of multiple endoderm-derived organ systems such as the liver, pancreas and lungs; FOXA1 and FOXA2 seem to have at least in part redundant roles. Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; regulates the expression of genes important for glucose sensing in pancreatic beta-cells and glucose homeostasis. Involved in regulation of fat metabolism. Binds to fibrinogen beta promoter and is involved in IL6-induced fibrinogen beta transcriptional activation.SUBUNIT Binds DNA as a monomer. Binds TLE1 (By similarity). Interacts with FOXA1 and FOXA3. Interacts with PRKDC.PTM Phosphorylation on Thr-156 abolishes binding to target promoters and subsequent transcription activation upon insulin stimulation. UniProt Q9Y261 1 EQUAL 457 EQUAL Reactome Database ID Release 81 211275 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=211275 Reactome R-HSA-211275 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-211275.1 LEFT-TO-RIGHT MAFA-, NKX2-2-, PAX6-, and PDX1-dependent synthesis of insulin precursor protein The INS1 gene, encoding insulin precursor protein, is transcribed and its mRNA is translated on membrane-associated ribosomes. INS1 transcription is positively regulated by the activities of the MAFA, NKX2-2, PAX6, and PDX1 transcription factors. These events and interactions are inferred from corresponding ones studied in molecular detail in the mouse. RFX6 binds an X box motif in the promoter of the insulin (INS) gene and transactivates transcription (Chandra et al. 2014). RFX6 also activates expression of genes encoding calcium channels. Missense mutations in RFX6 appear to cause neonatal diabetes. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 INS gene Reactome DB_ID: 8931792 ENSEMBL:ENSG00000254647 INS INS ENSEMBL ENSG00000254647 Reactome Database ID Release 81 8931792 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=8931792 Reactome R-HSA-8931792 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-8931792.1 Proinsulin INS(25-110) Reactome DB_ID: 264893 endoplasmic reticulum lumen GENE ONTOLOGY GO:0005788 UniProt:P01308 INS INS FUNCTION Insulin decreases blood glucose concentration. It increases cell permeability to monosaccharides, amino acids and fatty acids. It accelerates glycolysis, the pentose phosphate cycle, and glycogen synthesis in liver.SUBUNIT Heterodimer of a B chain and an A chain linked by two disulfide bonds (PubMed:25423173).PHARMACEUTICAL Available under the names Humulin or Humalog (Eli Lilly) and Novolin (Novo Nordisk). Used in the treatment of diabetes. Humalog is an insulin analog with 52-Lys-Pro-53 instead of 52-Pro-Lys-53.SIMILARITY Belongs to the insulin family. UniProt P01308 25 EQUAL 110 EQUAL Reactome Database ID Release 81 264893 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=264893 Reactome R-HSA-264893 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-264893.2 Reactome Database ID Release 81 211289 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=211289 Reactome R-HSA-211289 5 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-211289.5 ACTIVATION activeUnit: #Protein13 Reactome Database ID Release 81 8931800 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=8931800 Reactome R-HSA-8931800 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-8931800.1 RFX6:INS gene Reactome DB_ID: 8931797 RFX6 DNA-binding protein RFX6 RFX6_HUMAN Reactome DB_ID: 8931801 UniProt:Q8HWS3 RFX6 RFX6 RFXDC1 FUNCTION Transcription factor required to direct islet cell differentiation during endocrine pancreas development. Specifically required for the differentiation of 4 of the 5 islet cell types and for the production of insulin (PubMed:20148032, PubMed:25497100). Not required for pancreatic PP (polypeptide-producing) cells differentiation. Acts downstream of NEUROG3 and regulates the transcription factors involved in beta-cell maturation and function, thereby restricting the expression of the beta-cell differentiation and specification genes, and thus the beta-cell fate choice. Activates transcription by forming a heterodimer with RFX3 and binding to the X-box in the promoter of target genes (PubMed:20148032). Involved in glucose-stimulated insulin secretion by promoting insulin and L-type calcium channel gene transcription (PubMed:25497100).SUBUNIT Interacts with RFX3.TISSUE SPECIFICITY Expressed in pancreas (PubMed:25497100). Expressed in pancreatic beta-cells (insulin-positive cells) and alpha-cells (glucagon-positive cells) (at protein level). Specifically expressed in pancreas, small intestine and colon (PubMed:20148032). Expressed in endocrine cells in the islets (PubMed:25497100).SIMILARITY Belongs to the RFX family. UniProt Q8HWS3 1 EQUAL 928 EQUAL Reactome Database ID Release 81 8931801 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=8931801 Reactome R-HSA-8931801 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-8931801.1 1 1 Reactome Database ID Release 81 8931797 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=8931797 Reactome R-HSA-8931797 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-8931797.1 ACTIVATION Reactome Database ID Release 81 211287 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=211287 Reactome R-HSA-211287 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-211287.1 ACTIVATION Reactome Database ID Release 81 211358 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=211358 Reactome R-HSA-211358 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-211358.1 ACTIVATION Reactome Database ID Release 81 211290 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=211290 Reactome R-HSA-211290 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-211290.1 ACTIVATION Reactome Database ID Release 81 211292 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=211292 Reactome R-HSA-211292 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-211292.1 NKX2-2 NKX2.2 Reactome DB_ID: 186537 UniProt:O95096 NKX2-2 NKX2-2 NKX2.2 NKX2B FUNCTION Transcriptional activator involved in the development of insulin-producting beta cells in the endocrine pancreas (By similarity). May also be involved in specifying diencephalic neuromeric boundaries, and in controlling the expression of genes that play a role in axonal guidance. Binds to elements within the NEUROD1 promoter (By similarity).SUBUNIT Interacts with OLIG2.DOMAIN The homeodomain is essential for interaction with OLIG2.SIMILARITY Belongs to the NK-2 homeobox family. UniProt O95096 1 EQUAL 273 EQUAL Reactome Database ID Release 81 186537 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=186537 Reactome R-HSA-186537 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-186537.1 LEFT-TO-RIGHT PDX1-dependent synthesis of IAPP protein The IAPP gene, encoding islet amyloid precursor protein, is transcribed and its mRNA is translated. IAPP transcription is positively regulated by PDX1 transcription factor. These events and interactions are inferred from corresponding ones studied in molecular detail in the mouse. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 IAPP gene Reactome DB_ID: 9606123 ENSEMBL:ENSG00000121351 IAPP IAPP ENSEMBL ENSG00000121351 Reactome Database ID Release 81 9606123 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=9606123 Reactome R-HSA-9606123 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-9606123.1 IAPP IAPP(1-828) Islet amyloid polypeptide Amylin Reactome DB_ID: 186631 UniProt:P10997 IAPP IAPP FUNCTION Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism.SUBUNIT Interacts with IDE and INS. Can form homodimers. Interaction with INS inhibits homodimerization and fibril formation.DOMAIN The mature protein is largely unstructured in the absence of a cognate ligand, and has a strong tendency to form fibrillar aggregates. Homodimerization may be the first step of amyloid formation.PTM Amyloid fibrils are degraded by IDE.MISCELLANEOUS IAPP is the peptide subunit of amyloid found in pancreatic islets of type 2 diabetic patients and in insulinomas.SIMILARITY Belongs to the calcitonin family. UniProt P10997 1 EQUAL 828 EQUAL Reactome Database ID Release 81 186631 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=186631 Reactome R-HSA-186631 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-186631.1 Reactome Database ID Release 81 211301 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=211301 Reactome R-HSA-211301 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-211301.2 ACTIVATION Reactome Database ID Release 81 211304 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=211304 Reactome R-HSA-211304 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-211304.1 LEFT-TO-RIGHT PDX1-dependent synthesis of NKX6-1 protein In mature beta-cells of the pancreas, the NKX6-1 gene is transcribed, its mRNA is translated, and the protein product is transported to the nucleus. NKX6-1 transcription is positively regulated by the activity of the PDX1 transcription factor. These events and interactions have not been studied directly in humans, but are inferred from corresponding ones worked out in the mouse. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 NKX6-1 gene Reactome DB_ID: 9606121 ENSEMBL:ENSG00000163623 NKX6-1 NKX6-1 NKX6A ENSEMBL ENSG00000163623 Reactome Database ID Release 81 9606121 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=9606121 Reactome R-HSA-9606121 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-9606121.1 NKX6-1 Reactome DB_ID: 210765 UniProt:P78426 NKX6-1 NKX6-1 NKX6A FUNCTION Transcription factor which binds to specific A/T-rich DNA sequences in the promoter regions of a number of genes. Involved in the development of insulin-producing beta cells in the islets of Langerhans at the secondary transition (By similarity). Together with NKX2-2 and IRX3 acts to restrict the generation of motor neurons to the appropriate region of the neural tube. Belongs to the class II proteins of neuronal progenitor factors, which are induced by SHH signals (By similarity).TISSUE SPECIFICITY Pancreatic beta cells.DOMAIN The C-terminal domain contributes to sequence-specific DNA-binding. UniProt P78426 1 EQUAL 367 EQUAL Reactome Database ID Release 81 210765 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=210765 Reactome R-HSA-210765 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-210765.1 Reactome Database ID Release 81 211350 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=211350 Reactome R-HSA-211350 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-211350.2 ACTIVATION Reactome Database ID Release 81 211357 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=211357 Reactome R-HSA-211357 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-211357.1 LEFT-TO-RIGHT NEUROD1- and PDX1-dependent synthesis of glucokinase (GCK) protein The glucokinase (GCK) gene is transcribed and its mRNA is translated. GCK transcription is positively regulated by the activity of the NEUROD1 and PDX1 transcription factors. These events and interactions are inferred from corresponding ones studied in molecular detail in the mouse. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 GCK gene Reactome DB_ID: 9606120 ENSEMBL:ENSG00000106633 GCK GCK ENSEMBL ENSG00000106633 Reactome Database ID Release 81 9606120 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=9606120 Reactome R-HSA-9606120 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-9606120.1 GCK glucokinase Reactome DB_ID: 450094 UniProt:P35557 GCK GCK FUNCTION Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively) (PubMed:7742312, PubMed:11916951, PubMed:15277402, PubMed:17082186, PubMed:18322640, PubMed:19146401, PubMed:25015100, PubMed:8325892). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant (By similarity). Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues (PubMed:18322640, PubMed:25015100, PubMed:8325892, PubMed:11916951, PubMed:15277402). Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell (By similarity). In pancreas, plays an important role in modulating insulin secretion (By similarity). In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage (By similarity). Required to provide D-glucose 6-phosphate for the synthesis of glycogen (PubMed:8878425). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:7742312).ACTIVITY REGULATION Subject to allosteric regulation (PubMed:15016359). Low glucose and high fructose-6-phosphate triggers association with the inhibitor GCKR followed by sequestration in the nucleus (PubMed:10456334).PATHWAY Carbohydrate metabolism; hexose metabolism.PATHWAY Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 1/4.SUBUNIT Monomer (PubMed:15016359, PubMed:19362831, PubMed:23957911). Interacts with MIDN; the interaction occurs preferentially at low glucose levels and results in inhibition of hexokinase activity (PubMed:24187134). Interacts with GCKR; leading to sequestration in the nucleus (PubMed:10456334).SIMILARITY Belongs to the hexokinase family. UniProt P35557 1 EQUAL 465 EQUAL Reactome Database ID Release 81 450094 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=450094 Reactome R-HSA-450094 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-450094.1 Reactome Database ID Release 81 211346 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=211346 Reactome R-HSA-211346 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-211346.3 ACTIVATION Reactome Database ID Release 81 633894 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=633894 Reactome R-HSA-633894 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-633894.1 ACTIVATION Reactome Database ID Release 81 633895 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=633895 Reactome R-HSA-633895 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-633895.1 NEUROD1 NeuroD1/Beta2 Reactome DB_ID: 186689 UniProt:Q13562 NEUROD1 NEUROD1 BHLHA3 NEUROD FUNCTION Acts as a transcriptional activator: mediates transcriptional activation by binding to E box-containing promoter consensus core sequences 5'-CANNTG-3'. Associates with the p300/CBP transcription coactivator complex to stimulate transcription of the secretin gene as well as the gene encoding the cyclin-dependent kinase inhibitor CDKN1A. Contributes to the regulation of several cell differentiation pathways, like those that promote the formation of early retinal ganglion cells, inner ear sensory neurons, granule cells forming either the cerebellum or the dentate gyrus cell layer of the hippocampus, endocrine islet cells of the pancreas and enteroendocrine cells of the small intestine. Together with PAX6 or SIX3, is required for the regulation of amacrine cell fate specification. Also required for dendrite morphogenesis and maintenance in the cerebellar cortex. Associates with chromatin to enhancer regulatory elements in genes encoding key transcriptional regulators of neurogenesis (By similarity).SUBUNIT Efficient DNA-binding requires dimerization with another bHLH protein (By similarity). Heterodimer with TCF3/E47; the heterodimer is inhibited in presence of ID2, but not NR0B2, to E-box element (PubMed:14752053). Interacts with EP300; the interaction is inhibited by NR0B2 (PubMed:14752053). Interacts with RREB1 (PubMed:12482979). Interacts with ATOH8 (By similarity).PTM Phosphorylated. In islet cells, phosphorylated on Ser-274 upon glucose stimulation; which may be required for nuclear localization. In activated neurons, phosphorylated on Ser-335; which promotes dendritic growth. Phosphorylated by MAPK1; phosphorylation regulates heterodimerization and DNA-binding activities. Phosphorylation on Ser-266 and Ser-274 increases transactivation on the insulin promoter in glucose-stimulated insulinoma cells (By similarity). UniProt Q13562 1 EQUAL 356 EQUAL Reactome Database ID Release 81 186689 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=186689 Reactome R-HSA-186689 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-186689.1 LEFT-TO-RIGHT HNF1A-dependent synthesis of GLUT2 protein The GLUT2 gene is transcribed, its mRNA is translated, and the protein product is localized to the plasma membrane. GLUT2 expression is positively regulated by HNF1A. In vivo, pancreatic GLUT2 expression is positively regulated by HNF1A. Mutations in HNF1A are associated with a form of MODY (maturity onset diabetes of the young) (Fanjans et al. 2001) and interactions between the HNF1A protein product and the GLUT2 promoter have been demomstrated in vitro (Ban et al. 2002). However, the molecular details of GLUT2 expression in intact pancreatic beta cells have not been studied in humans, but are inferred from corresponding ones worked out in the mouse. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 SLC2A2 gene Reactome DB_ID: 9606135 ENSEMBL:ENSG00000163581 SLC2A2 SLC2A2 GLUT2 ENSEMBL ENSG00000163581 Reactome Database ID Release 81 9606135 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=9606135 Reactome R-HSA-9606135 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-9606135.1 GLUT2 SLC2A2 Solute carrier family 2, facilitated glucose transporter, member 2 Glucose transporter type 2, liver Reactome DB_ID: 70421 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:P11168 SLC2A2 SLC2A2 GLUT2 FUNCTION Facilitative hexose transporter that mediates the transport of glucose and fructose (PubMed:8027028, PubMed:16186102, PubMed:23396969, PubMed:28083649). Likely mediates the bidirectional transfer of glucose across the plasma membrane of hepatocytes and is responsible for uptake of glucose by the beta cells; may comprise part of the glucose-sensing mechanism of the beta cell (PubMed:8027028). May also participate with the Na(+)/glucose cotransporter in the transcellular transport of glucose in the small intestine and kidney (PubMed:3399500). Also able to mediate the transport of dehydroascorbate (PubMed:23396969).TISSUE SPECIFICITY Liver, insulin-producing beta cell, small intestine and kidney.PTM N-glycosylated; required for stability and retention at the cell surface of pancreatic beta cells.SIMILARITY Belongs to the major facilitator superfamily. Sugar transporter (TC 2.A.1.1) family. Glucose transporter subfamily. UniProt P11168 1 EQUAL 524 EQUAL Reactome Database ID Release 81 70421 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=70421 Reactome R-HSA-70421 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-70421.1 Reactome Database ID Release 81 211476 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=211476 Reactome R-HSA-211476 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-211476.2 11978637 Pubmed 2002 Hepatocyte nuclear factor-1alpha recruits the transcriptional co-activator p300 on the GLUT2 gene promoter Ban, N Yamada, Y Someya, Y Miyawaki, K Ihara, Y Hosokawa, M Toyokuni, S Tsuda, K Seino, Y Diabetes 51:1409-18 11575290 Pubmed 2001 Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young Fajans, SS Bell, Graeme I Polonsky, KS N Engl J Med 345:971-80 ACTIVATION Reactome Database ID Release 81 211497 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=211497 Reactome R-HSA-211497 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-211497.1 HNF1A Hepatocyte nuclear factor 1-alpha HNF1A_HUMAN Reactome DB_ID: 3004629 UniProt:P20823 HNF1A HNF1A TCF1 FUNCTION Transcriptional activator that regulates the tissue specific expression of multiple genes, especially in pancreatic islet cells and in liver (By similarity). Binds to the inverted palindrome 5'-GTTAATNATTAAC-3' (PubMed:12453420, PubMed:10966642). Activates the transcription of CYP1A2, CYP2E1 and CYP3A11 (By similarity).SUBUNIT Binds DNA as a dimer (PubMed:12453420). Heterotetramer with PCBD1; formed by a dimer of dimers (By similarity). Interacts with PCBD1 (PubMed:10966642). Interacts with BHLHE41 (By similarity).TISSUE SPECIFICITY Liver.POLYMORPHISM The Ala-98/Val-98 polymorphism is associated with a reduction in glucose-induced serum C-peptide and insulin responses.SIMILARITY Belongs to the HNF1 homeobox family. UniProt P20823 1 EQUAL 631 EQUAL Reactome Database ID Release 81 3004629 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=3004629 Reactome R-HSA-3004629 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-3004629.1 LEFT-TO-RIGHT HNF1A-dependent synthesis of the L isoform of PKLR protein The PKLR gene is transcribed, its mRNA is translated, spliced, and translated to yield the L isoform of PKLR protein. PKLR expression is positively regulated by HNF1A. Mutations in HNF1A are associated with a form of MODY (maturity onset diabetes of the young) (Fanjans et al. 2001) but the molecular details of PKLR expression in intact pancreatic beta cells have not been studied in humans, and are inferred from corresponding ones worked out in the mouse. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 PKLR gene Reactome DB_ID: 9606134 ENSEMBL:ENSG00000143627 PKLR PKLR PK1 PKL ENSEMBL ENSG00000143627 Reactome Database ID Release 81 9606134 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=9606134 Reactome R-HSA-9606134 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-9606134.1 PKLR-2 PKLR isozyme L PKLR isoform 2 Pyruvate kinase, L isozyme pyruvate kinase, liver and RBC Red cell/liver pyruvate kinase Reactome DB_ID: 211388 UniProt:P30613-2 PKLR PKLR PK1 PKL FUNCTION Plays a key role in glycolysis.ACTIVITY REGULATION Allosterically activated by fructose 1,6-bisphosphate.PATHWAY Carbohydrate degradation; glycolysis; pyruvate from D-glyceraldehyde 3-phosphate: step 5/5.SUBUNIT Homotetramer.MISCELLANEOUS There are 4 isozymes of pyruvate kinase in mammals: L, R, M1 and M2. L type is major isozyme in the liver, R is found in red cells, M1 is the main form in muscle, heart and brain, and M2 is found in early fetal tissues.SIMILARITY Belongs to the pyruvate kinase family. UniProt Isoform P30613-2 1 EQUAL 574 EQUAL Reactome Database ID Release 81 211388 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=211388 Reactome R-HSA-211388 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-211388.1 Reactome Database ID Release 81 211461 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=211461 Reactome R-HSA-211461 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-211461.2 ACTIVATION Reactome Database ID Release 81 211490 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=211490 Reactome R-HSA-211490 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-211490.1 LEFT-TO-RIGHT HNF1A-dependent synthesis of HNF4A The HNF4A gene is transcribed from either of two promoters, P1 and P2, the resulting mRNA is translated, and the protein products localize in the nucleoplasm. Transcription is positively regulated by HNF1A. Many of the molecular details of these events have not been studied experimentally in humans, but are inferred from mouse model systems (Boj et al. 2001). Transcription in mouse and human pancreatic beta cells is P2-dependent and in humans yields three isoforms of mature HNF4A protein. A point mutation in the human P2 genomic DNA sequence is associated with MODY (maturity onset diabetes of the young), consistent with the hypothesis that P2-mediated transcription is essential for HNF4A expression and normal beta cell function (Hansen et al. 2002). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 HNF4A gene Reactome DB_ID: 9606122 ENSEMBL:ENSG00000101076 HNF4A HNF4A HNF4 NR2A1 TCF14 ENSEMBL ENSG00000101076 Reactome Database ID Release 81 9606122 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=9606122 Reactome R-HSA-9606122 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-9606122.1 Converted from EntitySet in Reactome HNF-4-alpha HNF4A (pancreas-specific) Hepatocyte nuclear factor 4-alpha Transcription factor 14 Reactome DB_ID: 211468 HNF4A-5 HNF4A isoform 7 Reactome DB_ID: 211478 UniProt:P41235-5 HNF4A HNF4A HNF4 NR2A1 TCF14 FUNCTION Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes (PubMed:30597922). Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-ARNTL/BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698).SUBUNIT Homodimerization is required for HNF4-alpha to bind to its recognition site (PubMed:14982928). Interacts with CLOCK, ARNTL, CRY1, CRY2, PER1 and PER2 (PubMed:30530698). Interacts with NR0B2/SHP; the resulting heterodimer is transcriptionnally inactive (PubMed:28128295). Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (PubMed:28128295).DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Phosphorylated on tyrosine residue(s); phosphorylation is important for its DNA-binding activity. Phosphorylation may directly or indirectly play a regulatory role in the subnuclear distribution. Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA.PTM Acetylation at Lys-458 lowers transcriptional activation by about two-fold.MISCELLANEOUS Binds fatty acids.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily. UniProt Isoform P41235-5 1 EQUAL 452 EQUAL Reactome Database ID Release 81 211478 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=211478 Reactome R-HSA-211478 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-211478.1 HNF4A-6 HNF4A isoform 8 Reactome DB_ID: 211463 UniProt:P41235-6 HNF4A HNF4A HNF4 NR2A1 TCF14 FUNCTION Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes (PubMed:30597922). Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-ARNTL/BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698).SUBUNIT Homodimerization is required for HNF4-alpha to bind to its recognition site (PubMed:14982928). Interacts with CLOCK, ARNTL, CRY1, CRY2, PER1 and PER2 (PubMed:30530698). Interacts with NR0B2/SHP; the resulting heterodimer is transcriptionnally inactive (PubMed:28128295). Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (PubMed:28128295).DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Phosphorylated on tyrosine residue(s); phosphorylation is important for its DNA-binding activity. Phosphorylation may directly or indirectly play a regulatory role in the subnuclear distribution. Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA.PTM Acetylation at Lys-458 lowers transcriptional activation by about two-fold.MISCELLANEOUS Binds fatty acids.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily. UniProt Isoform P41235-6 1 EQUAL 442 EQUAL Reactome Database ID Release 81 211463 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=211463 Reactome R-HSA-211463 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-211463.1 HNF4A-7 HNF4A isoform 9 Reactome DB_ID: 211462 UniProt:P41235-7 HNF4A HNF4A HNF4 NR2A1 TCF14 FUNCTION Transcriptional regulator which controls the expression of hepatic genes during the transition of endodermal cells to hepatic progenitor cells, facilitating the recruitment of RNA pol II to the promoters of target genes (PubMed:30597922). Activates the transcription of CYP2C38 (By similarity). Represses the CLOCK-ARNTL/BMAL1 transcriptional activity and is essential for circadian rhythm maintenance and period regulation in the liver and colon cells (PubMed:30530698).SUBUNIT Homodimerization is required for HNF4-alpha to bind to its recognition site (PubMed:14982928). Interacts with CLOCK, ARNTL, CRY1, CRY2, PER1 and PER2 (PubMed:30530698). Interacts with NR0B2/SHP; the resulting heterodimer is transcriptionnally inactive (PubMed:28128295). Interacts with DDX3X; this interaction disrupts the interaction between HNF4 and NR0B2 that forms inactive heterodimers and enhances the formation of active HNF4 homodimers (PubMed:28128295).DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Phosphorylated on tyrosine residue(s); phosphorylation is important for its DNA-binding activity. Phosphorylation may directly or indirectly play a regulatory role in the subnuclear distribution. Phosphorylation at Ser-313 by AMPK reduces the ability to form homodimers and bind DNA.PTM Acetylation at Lys-458 lowers transcriptional activation by about two-fold.MISCELLANEOUS Binds fatty acids.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily. UniProt Isoform P41235-7 1 EQUAL 395 EQUAL Reactome Database ID Release 81 211462 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=211462 Reactome R-HSA-211462 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-211462.1 Reactome Database ID Release 81 211468 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=211468 Reactome R-HSA-211468 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-211468.1 Reactome Database ID Release 81 211466 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=211466 Reactome R-HSA-211466 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-211466.2 11717395 Pubmed 2001 A transcription factor regulatory circuit in differentiated pancreatic cells Boj, SF Parrizas, M Maestro, MA Ferrer, Jorge Proc Natl Acad Sci U S A 98:14481-6 12235114 Pubmed 2002 Genetic evidence that HNF-1alpha-dependent transcriptional control of HNF-4alpha is essential for human pancreatic beta cell function Hansen, SK Parrizas, M Jensen, ML Pruhova, S Ek, J Boj, SF Johansen, A Maestro, MA Rivera, F Eiberg, H Andel, M Lebl, J Pedersen, O Ferrer, Jorge Hansen, T J Clin Invest 110:827-33 ACTIVATION Reactome Database ID Release 81 211494 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=211494 Reactome R-HSA-211494 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-211494.1 LEFT-TO-RIGHT HNF1A-dependent synthesis of HNF4G protein The HNF4G gene is transcribed, its mRNA is translated, and the protein product is localized to the nucleoplasm. HNF4G expression is positively regulated by HNF1A. The molecular details of HNF4G expression in intact pancreatic beta cells have not been studied in humans, but are inferred from corresponding ones worked out in the mouse (Boj et al. 2001). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 HNF4G gene Reactome DB_ID: 9606126 ENSEMBL:ENSG00000164749 HNF4G HNF4G NR2A2 ENSEMBL ENSG00000164749 Reactome Database ID Release 81 9606126 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=9606126 Reactome R-HSA-9606126 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-9606126.1 HNF4G Hepatocyte nuclear factor 4-gamma Reactome DB_ID: 211483 UniProt:Q14541 HNF4G HNF4G NR2A2 FUNCTION Transcription factor. Has a lower transcription activation potential than HNF4-alpha.TISSUE SPECIFICITY Expressed in pancreas, kidney, small intestine and testis. Weakly expressed in colon. Not expressed in liver, skeletal muscle, lung, placenta, brain, heart, peripheral blood, ovary, prostate, thymus and spleen.SIMILARITY Belongs to the nuclear hormone receptor family. NR2 subfamily. UniProt Q14541 1 EQUAL 408 EQUAL Reactome Database ID Release 81 211483 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=211483 Reactome R-HSA-211483 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-211483.1 Reactome Database ID Release 81 211467 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=211467 Reactome R-HSA-211467 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-211467.2 ACTIVATION Reactome Database ID Release 81 211496 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=211496 Reactome R-HSA-211496 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-211496.1 LEFT-TO-RIGHT HNF1A-dependent synthesis of FOXA3 The FOXA3 gene is transcribed, its mRNA is translated, and the protein product is localized to the nucleoplasm. FOXA3 expression is positively regulated by HNF1A. The molecular details of FOXA3 expression in intact pancreatic beta cells have not been studied in humans, but are inferred from corresponding ones worked out in the mouse (Boj et al. 2001). Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 FOXA3 gene Reactome DB_ID: 9606124 ENSEMBL:ENSG00000170608 FOXA3 FOXA3 HNF3G TCF3G ENSEMBL ENSG00000170608 Reactome Database ID Release 81 9606124 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=9606124 Reactome R-HSA-9606124 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-9606124.1 FOXA3 Forkhead box protein A3 Hepatocyte nuclear factor 3-gamma Reactome DB_ID: 211484 UniProt:P55318 FOXA3 FOXA3 HNF3G TCF3G FUNCTION Transcription factor that is thought to act as a 'pioneer' factor opening the compacted chromatin for other proteins through interactions with nucleosomal core histones and thereby replacing linker histones at target enhancer and/or promoter sites (By similarity). Originally described as a transcription activator for a number of liver genes such as AFP, albumin, tyrosine aminotransferase, PEPCK, etc. Interacts with the cis-acting regulatory regions of these genes. Involved in glucose homeostasis; binds to and activates transcription from the G6PC1 promoter. Binds to the CYP3A4 promoter and activates its transcription in cooperation with CEBPA. Binds to the CYP3A7 promoter together with members of the CTF/NF-I family. Involved in regulation of neuronal-specific transcription. May be involved in regulation of spermatogenesis.SUBUNIT Interacts with FOXA2.TISSUE SPECIFICITY Expressed in erythroleukemia and hepatoma cell lines and in liver and pancreas. Not expressed in any other cell lines or tissues examined.DEVELOPMENTAL STAGE Detected in prenatal liver nuclear extracts (12.4-27 weeks estimated gestational age). Not detected in postnatal liver samples. UniProt P55318 1 EQUAL 350 EQUAL Reactome Database ID Release 81 211484 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=211484 Reactome R-HSA-211484 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-211484.1 Reactome Database ID Release 81 211482 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=211482 Reactome R-HSA-211482 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-211482.2 ACTIVATION Reactome Database ID Release 81 211493 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=211493 Reactome R-HSA-211493 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-211493.1 Reactome Database ID Release 81 210745 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=210745 Reactome R-HSA-210745 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-210745.1 12591178 Pubmed 2003 Transcription factors direct the development and function of pancreatic beta cells Chakrabarti, SK Mirmira, RG Trends Endocrinol Metab 14:78-84 15298336 Pubmed 2004 Transcriptional networks controlling pancreatic development and beta cell function Servitja, JM Ferrer, Jorge Diabetologia 47:597-613 GENE ONTOLOGY GO:0031018