BioPAX pathway converted from "NEUROD1- and PDX1-dependent synthesis of glucokinase (GCK) protein" in the Reactome database.LEFT-TO-RIGHTNEUROD1- and PDX1-dependent synthesis of glucokinase (GCK) proteinThe 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, 2008-05-23Reviewed: Jensen, J, 2008-05-12 21:46:53Edited: D'Eustachio, P, 2008-05-12 21:43:33GCK geneReactome DB_ID: 9606120nucleoplasmGENE ONTOLOGYGO:0005654ENSEMBL:ENSG00000106633 GCKGCKHomo sapiensNCBI Taxonomy9606ENSEMBLENSG00000106633Reactome Database ID Release 759606120Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9606120ReactomeR-HSA-96061201Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9606120.1Reactomehttp://www.reactome.orgGCKglucokinaseReactome DB_ID: 450094cytosolGENE ONTOLOGYGO:0005829UniProt:P35557 GCKGCKFUNCTION 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.UniProtP355571EQUAL465EQUALReactome Database ID Release 75450094Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=450094ReactomeR-HSA-4500941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-450094.1Reactome Database ID Release 75211346Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211346ReactomeR-HSA-2113463Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-211346.3ACTIVATIONReactome Database ID Release 75633895Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=633895ReactomeR-HSA-6338951Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-633895.1NEUROD1NeuroD1/Beta2Reactome DB_ID: 186689UniProt:Q13562 NEUROD1NEUROD1BHLHA3NEURODFUNCTION 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 Interacts (via helix-loop-helix motif domain) with EP300 (via C-terminus) (By similarity). Heterodimer with TCF3/E47; the heterodimer is inhibited in presence of ID2, but not NR0B2, to E-box element. Efficient DNA-binding requires dimerization with another bHLH protein. Interacts with RREB1. Interacts with EP300; the interaction is inhibited by NR0B2. Interacts with TCF3; the interaction is inhibited by ID2. 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).UniProtQ135621EQUAL356EQUALReactome Database ID Release 75186689Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=186689ReactomeR-HSA-1866891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-186689.1ACTIVATIONReactome Database ID Release 75633894Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=633894ReactomeR-HSA-6338941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-633894.1PDX1IPF1Reactome DB_ID: 211179UniProt:P52945 PDX1PDX1IPF1STF1FUNCTION 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.UniProtP529451EQUAL283EQUALReactome Database ID Release 75211179Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=211179ReactomeR-HSA-2111791Reactome stable identifier. Use this URL 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