BioPAX pathway converted from "Gastrin-CREB signalling pathway via PKC and MAPK" in the Reactome database. Gastrin-CREB signalling pathway via PKC and MAPK Gastrin-CREB signalling pathway via PKC and MAPK Gastrin is a hormone whose main function is to stimulate secretion of hydrochloric acid by the gastric mucosa, which results in gastrin formation inhibition. This hormone also acts as a mitogenic factor for gastrointestinal epithelial cells. Gastrin has two biologically active peptide forms, G34 and G17.Gastrin gene expression is upregulated in both a number of pre-malignant conditions and in established cancer through a variety of mechanisms. Depending on the tissue where it is expressed and the level of expression, differential processing of the polypeptide product leads to the production of different biologically active peptides. In turn, acting through the classical gastrin cholecystokinin B receptor CCK-BR, its isoforms and alternative receptors, these peptides trigger signalling pathways which influence the expression of downstream genes that affect cell survival, angiogenesis and invasion (Wank 1995, de Weerth et al. 1999, Grabowska & Watson 2007) Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Gastrin binds to CCK-B receptor Gastrin binds to CCK-B receptor Gastrin receptors (gastric cholecystokinin B receptor, CCK-BR) mediate acid secretion from parietal cells, release of histamine from enterochromaffin-like (ECL) cells and contraction of smooth muscle (Ito et al. 1993).The hormone gastrin is the central regulator of gastric acid secretion and in addition, plays a prominent role in regulation of growth and differentiation of gastric and colonic mucosa. Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Reactome DB_ID: 870266 1 extracellular region GO 0005576 UniProt:P01350 GAST GAST GAS GAST FUNCTION Gastrin stimulates the stomach mucosa to produce and secrete hydrochloric acid and the pancreas to secrete its digestive enzymes. It also stimulates smooth muscle contraction and increases blood circulation and water secretion in the stomach and intestine.PTM Two different processing pathways probably exist in antral G-cells. In the dominant pathway progastrin is cleaved at three sites resulting in two major bioactive gastrins, gastrin-34 and gastrin-17. In the putative alternative pathway, progastrin may be processed only at the most C-terminal dibasic site resulting in the synthesis of gastrin-71.PTM Sulfation enhances proteolytic processing, and blocks peptide degradation. Levels of sulfation differ between proteolytically-cleaved gastrins. Thus, gastrin-6 is almost 73% sulfated, whereas the larger gastrins are less than 50% sulfated. Sulfation levels are also tissue-specific.SIMILARITY Belongs to the gastrin/cholecystokinin family. Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 UniProt P01350 Chain Coordinates 76 EQUAL 92 EQUAL Reactome DB_ID: 388515 1 plasma membrane GO 0005886 UniProt:P32239 CCKBR CCKBR CCKBR CCKRB FUNCTION Receptor for gastrin and cholecystokinin. The CCK-B receptors occur throughout the central nervous system where they modulate anxiety, analgesia, arousal, and neuroleptic activity. This receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.FUNCTION Isoform 2 is constitutively activated and may regulate cancer cell proliferation via a gastrin-independent mechanism.TISSUE SPECIFICITY Isoform 1 is expressed in brain, pancreas, stomach, the colon cancer cell line LoVo and the T-lymphoblastoma Jurkat, but not in heart, placenta, liver, lung, skeletal muscle, kidney or the stomach cancer cell line AGS. Expressed at high levels in the small cell lung cancer cell line NCI-H510, at lower levels in NCI-H345, NCI-H69 and GLC-28 cell lines, not expressed in GLC-19 cell line. Within the stomach, expressed at high levels in the mucosa of the gastric fundus and at low levels in the antrum and duodenum. Isoform 2 is present in pancreatic cancer cells and colorectal cancer cells, but not in normal pancreas or colonic mucosa. Isoform 3 is expressed in brain, pancreas, stomach, the stomach cancer cell line AGS and the colon cancer cell line LoVo.SIMILARITY Belongs to the G-protein coupled receptor 1 family. UniProt P32239 1 EQUAL 447 EQUAL Reactome DB_ID: 870262 1 Gastrin:CCKBR [plasma membrane] Gastrin:CCKBR Reactome DB_ID: 870266 1 76 EQUAL 92 EQUAL Reactome DB_ID: 388515 1 1 EQUAL 447 EQUAL Reactome Database ID Release 81 870262 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=870262 Reactome R-HSA-870262 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-870262.1 Reactome Database ID Release 81 870269 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=870269 Reactome R-HSA-870269 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-870269.1 8349705 Pubmed 1993 Functional characterization of a human brain cholecystokinin-B receptor. A trophic effect of cholecystokinin and gastrin Ito, M Matsui, T Taniguchi, T Tsukamoto, T Murayama, T Arima, N Nakata, H Chiba, T Chihara, K J Biol Chem 268:18300-5 EGFR Transactivation by Gastrin EGFR Transactivation by Gastrin Gastrin, through the action of diacylglycerol produced from downstream G alpha (q) events, transactivates EGFR via a PKC-mediated pathway by activation of MMP3 (Matrix Metalloproteinase 3) which allows formation of mature HBEGF (heparin-binding epidermal growth factor) by cleaving pro-HBEGF. Mature HBEGF is then free to bind the EGFR, resulting in EGFR activation (Dufresne et al. 2006, Liebmann 2011). Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Diacylgycerol activates Protein kinase C, alpha type Diacylgycerol activates Protein kinase C, alpha type Diacylglycerol, produced by PLC beta-mediated PIP2 hydrolysis in G alpha (q) signalling, remains in the plasma membrane and binds Protein Kinase C alpha (PKC-alpha), causing PKC-alpha to translocate from the cytosol to the plasma membrane. PKC-alpha is thereby activated and phosphorylates target proteins. Authored: May, B, 2009-05-28 03:44:04 Reviewed: Gillespie, ME, 2009-06-02 00:56:21 Edited: May, B, 2009-05-28 03:44:04 Reactome DB_ID: 114519 1 1,2-diacyl-sn-glycerol [ChEBI:17815] 1,2-diacyl-sn-glycerol ChEBI 17815 Reactome DB_ID: 58196 1 cytosol GO 0005829 UniProt:P17252 PRKCA PRKCA PRKCA PKCA PRKACA FUNCTION Calcium-activated, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that is involved in positive and negative regulation of cell proliferation, apoptosis, differentiation, migration and adhesion, tumorigenesis, cardiac hypertrophy, angiogenesis, platelet function and inflammation, by directly phosphorylating targets such as RAF1, BCL2, CSPG4, TNNT2/CTNT, or activating signaling cascade involving MAPK1/3 (ERK1/2) and RAP1GAP. Involved in cell proliferation and cell growth arrest by positive and negative regulation of the cell cycle. Can promote cell growth by phosphorylating and activating RAF1, which mediates the activation of the MAPK/ERK signaling cascade, and/or by up-regulating CDKN1A, which facilitates active cyclin-dependent kinase (CDK) complex formation in glioma cells. In intestinal cells stimulated by the phorbol ester PMA, can trigger a cell cycle arrest program which is associated with the accumulation of the hyper-phosphorylated growth-suppressive form of RB1 and induction of the CDK inhibitors CDKN1A and CDKN1B. Exhibits anti-apoptotic function in glioma cells and protects them from apoptosis by suppressing the p53/TP53-mediated activation of IGFBP3, and in leukemia cells mediates anti-apoptotic action by phosphorylating BCL2. During macrophage differentiation induced by macrophage colony-stimulating factor (CSF1), is translocated to the nucleus and is associated with macrophage development. After wounding, translocates from focal contacts to lamellipodia and participates in the modulation of desmosomal adhesion. Plays a role in cell motility by phosphorylating CSPG4, which induces association of CSPG4 with extensive lamellipodia at the cell periphery and polarization of the cell accompanied by increases in cell motility. During chemokine-induced CD4(+) T cell migration, phosphorylates CDC42-guanine exchange factor DOCK8 resulting in its dissociation from LRCH1 and the activation of GTPase CDC42 (PubMed:28028151). Is highly expressed in a number of cancer cells where it can act as a tumor promoter and is implicated in malignant phenotypes of several tumors such as gliomas and breast cancers. Negatively regulates myocardial contractility and positively regulates angiogenesis, platelet aggregation and thrombus formation in arteries. Mediates hypertrophic growth of neonatal cardiomyocytes, in part through a MAPK1/3 (ERK1/2)-dependent signaling pathway, and upon PMA treatment, is required to induce cardiomyocyte hypertrophy up to heart failure and death, by increasing protein synthesis, protein-DNA ratio and cell surface area. Regulates cardiomyocyte function by phosphorylating cardiac troponin T (TNNT2/CTNT), which induces significant reduction in actomyosin ATPase activity, myofilament calcium sensitivity and myocardial contractility. In angiogenesis, is required for full endothelial cell migration, adhesion to vitronectin (VTN), and vascular endothelial growth factor A (VEGFA)-dependent regulation of kinase activation and vascular tube formation. Involved in the stabilization of VEGFA mRNA at post-transcriptional level and mediates VEGFA-induced cell proliferation. In the regulation of calcium-induced platelet aggregation, mediates signals from the CD36/GP4 receptor for granule release, and activates the integrin heterodimer ITGA2B-ITGB3 through the RAP1GAP pathway for adhesion. During response to lipopolysaccharides (LPS), may regulate selective LPS-induced macrophage functions involved in host defense and inflammation. But in some inflammatory responses, may negatively regulate NF-kappa-B-induced genes, through IL1A-dependent induction of NF-kappa-B inhibitor alpha (NFKBIA/IKBA). Upon stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA), phosphorylates EIF4G1, which modulates EIF4G1 binding to MKNK1 and may be involved in the regulation of EIF4E phosphorylation. Phosphorylates KIT, leading to inhibition of KIT activity. Phosphorylates ATF2 which promotes cooperation between ATF2 and JUN, activating transcription. Phosphorylates SOCS2 at 'Ser-52' facilitating its ubiquitination and proteosomal degradation (By similarity).ACTIVITY REGULATION Classical (or conventional) PKCs (PRKCA, PRKCB and PRKCG) are activated by calcium and diacylglycerol (DAG) in the presence of phosphatidylserine. Three specific sites; Thr-497 (activation loop of the kinase domain), Thr-638 (turn motif) and Ser-657 (hydrophobic region), need to be phosphorylated for its full activation.SUBUNIT Recruited in a circadian manner into a nuclear complex which also includes BMAL1 and RACK1 (By similarity). Interacts with ADAP1/CENTA1 (PubMed:12893243). Interacts with CSPG4 (PubMed:15504744). Binds to CAVIN2 in the presence of phosphatidylserine (By similarity). Interacts with PRKCABP/PICK1 (via PDZ domain) (PubMed:15247289). Interacts with TRIM41 (PubMed:17893151). Interacts with PARD3 (PubMed:27925688). Interacts with SOCS2 (By similarity).SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily. UniProt P17252 2 EQUAL 672 EQUAL Reactome DB_ID: 422275 1 Protein Kinase C, alpha type: DAG [plasma membrane] Protein Kinase C, alpha type: DAG Reactome DB_ID: 114519 1 Reactome DB_ID: 58196 1 2 EQUAL 672 EQUAL Reactome Database ID Release 81 422275 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=422275 Reactome R-HSA-422275 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-422275.2 Reactome Database ID Release 81 400015 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=400015 Reactome R-HSA-400015 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-400015.2 11997388 Pubmed 2002 Interplay between calcium, diacylglycerol, and phosphorylation in the spatial and temporal regulation of PKCalpha-GFP Tanimura, Akihiko Nezu, Akihiro Morita, Takao Hashimoto, Noboru Tojyo, Yosuke J. Biol. Chem. 277:29054-62 11588141 Pubmed 2001 Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function Gilon, P Henquin, JC Endocr Rev 22:565-604 2.7.11.13 Activated PKC-alpha activate MMP3 Activated PKC-alpha activate MMP3 Gastrin activated PKC pathway leads to the induction of matrix metalloproteinase 3 (MMP3) synthesis (Reuben et al. 2002). The cleavage and autocatalysis steps to obtain the fully activated form of MMP3 have been omitted here. Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Reactome DB_ID: 8943665 1 UniProt:P08254 MMP3 MMP3 MMP3 STMY1 FUNCTION Can degrade fibronectin, laminin, gelatins of type I, III, IV, and V; collagens III, IV, X, and IX, and cartilage proteoglycans. Activates procollagenase.DOMAIN The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.SIMILARITY Belongs to the peptidase M10A family. UniProt P08254 1 EQUAL 477 EQUAL Reactome DB_ID: 1430778 1 100 EQUAL 477 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 422275 GO 0004697 GO molecular function Reactome Database ID Release 81 2179399 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=2179399 Reactome Database ID Release 81 2179413 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=2179413 Reactome R-HSA-2179413 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-2179413.2 11836255 Pubmed 2002 Molecular mechanism of the induction of metalloproteinases 1 and 3 in human fibroblasts by basic calcium phosphate crystals. Role of calcium-dependent protein kinase C alpha Reuben, PM Brogley, MA Sun, Y Cheung, HS J Biol Chem 277:15190-8 3.4.24.64 3.4.24.21 3.4.24.11 3.4.24.22 3.4.24.55 3.4.24.70 3.4.24.71 3.4.24.61 3.4.24.72 3.4.24.17 3.4.24.18 3.4.24.19 3.4.24.23 3.4.24.56 3.4.24.24 3.4.24.35 3.4.24.57 3.4.24.14 3.4.24.69 3.4.24.37 3.4.24.59 Active MMP3 can cleave pro-HBEGF to form active HBEGF Active MMP3 can cleave pro-HBEGF to form active HBEGF Gastrin can induce cleavage of pro-HBEGF via MMP3, releasing mature HBEGF. This event is based on evidence from mouse experiments (Suzuki et al. 1997). Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Reactome DB_ID: 2179406 1 UniProt:Q99075 HBEGF HBEGF DTS DTR HEGFL HBEGF FUNCTION Growth factor that mediates its effects via EGFR, ERBB2 and ERBB4. Required for normal cardiac valve formation and normal heart function. Promotes smooth muscle cell proliferation. May be involved in macrophage-mediated cellular proliferation. It is mitogenic for fibroblasts, but not endothelial cells. It is able to bind EGF receptor/EGFR with higher affinity than EGF itself and is a far more potent mitogen for smooth muscle cells than EGF. Also acts as a diphtheria toxin receptor.SUBUNIT Interacts with FBLN1 (By similarity). Interacts with EGFR and ERBB4.PTM Several N-termini have been identified by direct sequencing. The forms with N-termini 63, 73 and 74 have been tested and found to be biologically active.PTM O-glycosylated with core 1 or possibly core 8 glycans. Thr-47 is a minor glycosylation site compared to Thr-44. UniProt Q99075 20 EQUAL 208 EQUAL Reactome DB_ID: 1233234 1 63 EQUAL 148 EQUAL Reactome DB_ID: 2179391 1 149 EQUAL 208 EQUAL Reactome DB_ID: 2179390 1 20 EQUAL 62 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 1430778 100 EQUAL 477 EQUAL GO 0004222 GO molecular function Reactome Database ID Release 81 2179412 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=2179412 Reactome Database ID Release 81 2179402 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=2179402 Reactome R-HSA-2179402 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-2179402.1 9395517 Pubmed 1997 Matrix metalloproteinase-3 releases active heparin-binding EGF-like growth factor by cleavage at a specific juxtamembrane site Suzuki, M Raab, Gerhard Moses, MA Fernandez, CA Klagsbrun, Michael J Biol Chem 272:31730-7 Mature HBEGF binds to EGFR, triggering dimerisation and autophosphorylation of the receptor Mature HBEGF binds to EGFR, triggering dimerisation and autophosphorylation of the receptor The heparin-binding EGF growth factor (HBEGF) is a member of the EGF family of growth factors that binds to and activates the EGF receptor EGFR/ErbB1 and ErbB4 (not shown here) (Higashiyama et al. 1991, Elenius et al. 1997). The details which describe receptor dimerisation on ligand binding and autophosphorylation from experiments in mice have been omitted here. Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Reactome DB_ID: 179837 1 UniProt:P00533 EGFR EGFR ERBB1 ERBB HER1 EGFR FUNCTION Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses (PubMed:2790960, PubMed:10805725, PubMed:27153536). Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF (PubMed:2790960, PubMed:7679104, PubMed:8144591, PubMed:9419975, PubMed:15611079, PubMed:12297049, PubMed:27153536, PubMed:20837704, PubMed:17909029). Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues. The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules (PubMed:27153536). May also activate the NF-kappa-B signaling cascade (PubMed:11116146). Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling (PubMed:11602604). Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin (PubMed:11483589). Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration (PubMed:20462955). Plays a role in enhancing learning and memory performance (By similarity).FUNCTION Isoform 2 may act as an antagonist of EGF action.FUNCTION (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry. Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins.ACTIVITY REGULATION Endocytosis and inhibition of the activated EGFR by phosphatases like PTPRJ and PTPRK constitute immediate regulatory mechanisms. Upon EGF-binding phosphorylates EPS15 that regulates EGFR endocytosis and activity. Moreover, inducible feedback inhibitors including LRIG1, SOCS4, SOCS5 and ERRFI1 constitute alternative regulatory mechanisms for the EGFR signaling. Up-regulated by NEU3-mediated desialylation of N-linked glycan at Asn-528.SUBUNIT Binding of the ligand triggers homo- and/or heterodimerization of the receptor triggering its autophosphorylation. Heterodimer with ERBB2 (PubMed:10805725). Forms a complex with CCDC88A/GIV (via SH2-like regions) and GNAI3 which leads to enhanced EGFR signaling and triggering of cell migration; binding to CCDC88A requires autophosphorylation of the EGFR C-terminal region, and ligand stimulation is required for recruitment of GNAI3 to the complex (PubMed:20462955, PubMed:25187647). Interacts with ERRFI1; inhibits dimerization of the kinase domain and autophosphorylation (PubMed:18046415). Part of a complex with ERBB2 and either PIK3C2A or PIK3C2B (PubMed:10805725). Interacts with GRB2; an adapter protein coupling the receptor to downstream signaling pathways. Interacts with GAB2; involved in signaling downstream of EGFR. Interacts with STAT3; mediates EGFR downstream signaling in cell proliferation. Interacts with RIPK1; involved in NF-kappa-B activation. Interacts (autophosphorylated) with CBL, CBLB and CBLC; involved in EGFR ubiquitination and regulation. Interacts with SOCS5; regulates EGFR degradation through ELOC- and ELOB-mediated ubiquitination and proteasomal degradation. Interacts with PRMT5; methylates EGFR and enhances interaction with PTPN6. Interacts (phosphorylated) with PTPN6; inhibits EGFR-dependent activation of MAPK/ERK. Interacts with COPG1; essential for regulation of EGF-dependent nuclear transport of EGFR by retrograde trafficking from the Golgi to the ER. Interacts with TNK2; this interaction is dependent on EGF stimulation and kinase activity of EGFR. Interacts with PCNA; positively regulates PCNA (PubMed:17115032). Interacts with PELP1. Interacts with MUC1. Interacts with AP2M1. Interacts with FER. May interact with EPS8; mediates EPS8 phosphorylation. Interacts (via SH2 domains) with GRB2, NCK1 and NCK2 (PubMed:10026169). Interacts with ATXN2. Interacts with GAREM1. Interacts (ubiquitinated) with ANKRD13A/B/D; the interaction is direct and may regulate EGFR internalization after EGF stimulation. Interacts with GPER1; the interaction occurs in an estrogen-dependent manner. Interacts (via C-terminal cytoplasmic kinase domain) with ZPR1 (via zinc fingers). Interacts with RNF115 and RNF126 (PubMed:23418353). Interacts with GPRC5A (via its transmembrane domain) (PubMed:25311788). Interacts with FAM83B; positively regulates EGFR inducing its autophosphorylation in absence of stimulation by EGF (PubMed:23912460). Interacts with LAPTM4B; positively correlates with EGFR activation (PubMed:28479384). Interacts with STX19 (PubMed:16420529). Interacts with CD44 (PubMed:23589287). Interacts with PGRMC1; the interaction requires PGRMC1 homodimerization (PubMed:26988023). Interacts with PIKFYVE (PubMed:17909029). Interacts with NEU3. Interacts with TRAF4 (PubMed:30352854).TISSUE SPECIFICITY Ubiquitously expressed. Isoform 2 is also expressed in ovarian cancers.PTM Phosphorylated on Tyr residues in response to EGF (PubMed:20462955, PubMed:27153536). Phosphorylation at Ser-695 is partial and occurs only if Thr-693 is phosphorylated. Phosphorylation at Thr-678 and Thr-693 by PRKD1 inhibits EGF-induced MAPK8/JNK1 activation. Dephosphorylation by PTPRJ prevents endocytosis and stabilizes the receptor at the plasma membrane. Autophosphorylation at Tyr-1197 is stimulated by methylation at Arg-1199 and enhances interaction with PTPN6. Autophosphorylation at Tyr-1092 and/or Tyr-1110 recruits STAT3. Dephosphorylated by PTPN1 and PTPN2.PTM Monoubiquitinated and polyubiquitinated upon EGF stimulation; which does not affect tyrosine kinase activity or signaling capacity but may play a role in lysosomal targeting (PubMed:27153536). Polyubiquitin linkage is mainly through 'Lys-63', but linkage through 'Lys-48', 'Lys-11' and 'Lys-29' also occurs. Deubiquitination by OTUD7B prevents degradation. Ubiquitinated by RNF115 and RNF126 (By similarity).PTM Palmitoylated on Cys residues by ZDHHC20. Palmitoylation inhibits internalization after ligand binding, and increases the persistence of tyrosine-phosphorylated EGFR at the cell membrane. Palmitoylation increases the amplitude and duration of EGFR signaling.PTM Methylated. Methylation at Arg-1199 by PRMT5 stimulates phosphorylation at Tyr-1197.SIMILARITY Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. UniProt P00533 25 EQUAL 1210 EQUAL Reactome DB_ID: 1233234 1 63 EQUAL 148 EQUAL Reactome DB_ID: 2179410 1 HB-EGF:p-6Y-EGFR dimer [plasma membrane] HB-EGF:p-6Y-EGFR dimer Reactome DB_ID: 2179388 2 HB-EGF:p-6Y-EGFR [plasma membrane] HB-EGF:p-6Y-EGFR Reactome DB_ID: 179803 1 O4'-phospho-L-tyrosine at 992 992 EQUAL O4'-phospho-L-tyrosine [MOD:00048] O4'-phospho-L-tyrosine at 1045 1045 EQUAL O4'-phospho-L-tyrosine at 1068 1068 EQUAL O4'-phospho-L-tyrosine at 1086 1086 EQUAL O4'-phospho-L-tyrosine at 1148 1148 EQUAL O4'-phospho-L-tyrosine at 1173 1173 EQUAL 25 EQUAL 1210 EQUAL Reactome DB_ID: 1233234 1 63 EQUAL 148 EQUAL Reactome Database ID Release 81 2179388 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=2179388 Reactome R-HSA-2179388 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-2179388.1 Reactome Database ID Release 81 2179410 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=2179410 Reactome R-HSA-2179410 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-2179410.1 Reactome Database ID Release 81 2179387 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=2179387 Reactome R-HSA-2179387 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-2179387.1 9135143 Pubmed 1997 Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation Elenius, K Paul, S Allison, G Sun, J Klagsbrun, Michael EMBO J 16:1268-78 1840698 Pubmed 1991 A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF Higashiyama, S Abraham, JA Miller, J Fiddes, JC Klagsbrun, Michael Science 251:936-9 GRB2:SOS1 binds to HBEGF:p-Y-EGFR GRB2:SOS1 binds to HBEGF:p-Y-EGFR Cytoplasmic target proteins containing the SH2 domain can bind to activated EGFR. One such protein, growth factor receptor-bound protein 2 (GRB2), can bind activated EGFR with its SH2 domain whilst in complex with SOS through its SH3 domain. GRB2 can bind at either Y1068 and/or Y1086 autophosphorylation sites on the receptor (Batzer et al. 1994, Okutani et al. 1994). Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Reactome DB_ID: 2179410 1 Reactome DB_ID: 109797 1 GRB2-1:SOS1 [cytosol] GRB2-1:SOS1 Reactome DB_ID: 64847 1 UniProt:Q07889 SOS1 SOS1 SOS1 FUNCTION Promotes the exchange of Ras-bound GDP by GTP (PubMed:8493579). Probably by promoting Ras activation, regulates phosphorylation of MAP kinase MAPK3 in response to EGF (PubMed:17339331). Catalytic component of a trimeric complex that participates in transduction of signals from Ras to Rac by promoting the Rac-specific guanine nucleotide exchange factor (GEF) activity (By similarity).SUBUNIT Interacts (via C-terminus) with GRB2 (via SH3 domain) (PubMed:8493579, PubMed:7664271). Forms a complex with phosphorylated MUC1 and GRB2 (via its SH3 domains) (PubMed:7664271). Interacts with phosphorylated LAT2 (PubMed:12486104). Interacts with NCK1 and NCK2 (PubMed:10026169). Part of a complex consisting of ABI1, EPS8 and SOS1 (By similarity). Interacts (Ser-1134 and Ser-1161 phosphorylated form) with YWHAB and YWHAE (PubMed:22827337).TISSUE SPECIFICITY Expressed in gingival tissues.PTM Phosphorylation at Ser-1134 and Ser-1161 by RPS6KA3 create YWHAB and YWHAE binding sites and which contribute to the negative regulation of EGF-induced MAPK1/3 phosphorylation. UniProt Q07889 1 EQUAL 1333 EQUAL Reactome DB_ID: 74686 1 UniProt:P62993-1 GRB2 GRB2 ASH GRB2 FUNCTION Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway.SUBUNIT Associates (via SH2 domain) with activated EGF and PDGF receptors (tyrosine phosphorylated) (PubMed:10026169, PubMed:19836242). Interacts with PDGFRA (tyrosine phosphorylated); the interaction may be indirect (By similarity). Also associates to other cellular Tyr-phosphorylated proteins such as SIT1, IRS1, IRS4, SHC and LNK; probably via the concerted action of both its SH2 and SH3 domains (PubMed:8388384, PubMed:8491186, PubMed:9553137, PubMed:11433379). It also seems to interact with RAS in the signaling pathway leading to DNA synthesis. Interacts with SOS1 (PubMed:8493579, PubMed:7664271). Forms a complex with MUC1 and SOS1, through interaction of the SH3 domains with SOS1 and the SH2 domain with phosphorylated MUC1 (PubMed:7664271). Interacts with phosphorylated MET (PubMed:11063574, PubMed:11827484). Interacts with phosphorylated TOM1L1 (By similarity). Interacts with the phosphorylated C-terminus of SH2B2 (PubMed:9233773). Interacts with phosphorylated SIT1, LAX1, LAT, LAT2 and LIME1 upon TCR and/or BCR activation (By similarity) (PubMed:9489702, PubMed:12359715, PubMed:12486104, PubMed:12514734). Interacts with NISCH, PTPNS1 and REPS2 (PubMed:9062191, PubMed:9422736, PubMed:11912194). Interacts with syntrophin SNTA1 (By similarity). Interacts (via SH3 domains) with REPS1 (By similarity). Interacts (via SH3 domains) with PIK3C2B (PubMed:11533253). Interacts with CBL and CBLB (PubMed:10022120, PubMed:10086340). Interacts with AJUBA and CLNK (By similarity). Interacts (via SH2 domain) with TEK/TIE2 (tyrosine phosphorylated) (By similarity). Interacts with SHB, INPP5D/SHIP1, SKAP1 and SKAP2 (PubMed:8723348, PubMed:9108392, PubMed:9484780, PubMed:10942756, PubMed:12171928). Interacts with PTPN11 (By similarity). Interacts with PRNP (By similarity). Interacts with RALGPS1 (PubMed:10747847). Interacts with HCST (PubMed:16582911). Interacts with KDR (By similarity). Interacts with FLT1 (tyrosine-phosphorylated) (By similarity). Interacts with GAPT and PTPRE (PubMed:10980613, PubMed:18559951). Interacts (via SH2 domain) with KIF26A (PubMed:19914172). Interacts (via SH3 2) with GAB2 (PubMed:19523899). Interacts with ADAM15 (PubMed:18296648). Interacts with THEMIS2 (By similarity). Interacts (via SH2 domain) with AXL (phosphorylated) (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with KIT (phosphorylated) (PubMed:15526160, PubMed:16129412). Interacts with PTPRJ and BCR (PubMed:12475979, PubMed:15302586). Interacts with PTPN23 (PubMed:21179510). Interacts with FLT4 (tyrosine phosphorylated) (PubMed:15102829). Interacts with EPHB1 and SHC1; activates the MAPK/ERK cascade to regulate cell migration (PubMed:8798570, PubMed:12925710). Part of a complex including TNK2, GRB2, LTK and one receptor tyrosine kinase (RTK) such as AXL and PDGFRL, in which GRB2 promotes RTK recruitment by TNK2 (PubMed:9178760, PubMed:19815557). Interacts (via SH2 domain) with CSF1R (tyrosine phosphorylated) (PubMed:8262059). Interacts with ERBB4 (PubMed:10867024). Interacts with NTRK1 (phosphorylated upon ligand-binding) (PubMed:15488758). Interacts with PTK2/FAK1 (tyrosine phosphorylated) (PubMed:9148935). Interacts with PTK2B/PYK2 (tyrosine phosphorylated) (PubMed:20521079). Interacts (via SH3 domains) with GAREM1 isoform 1 (via proline-rich domain and tyrosine phosphorylated); the interaction occurs upon EGF stimulation (PubMed:19509291). Interacts with DAB2 (By similarity). Interacts with TESPA1 (PubMed:22561606). Interacts with PLCG1, LAT and THEMIS upon TCR activation in thymocytes; the association is weaker in the absence of TESPA1 (By similarity). Interacts with CD28 (PubMed:24098653). Interacts with RAB13; may recruit RAB13 to the leading edge of migrating endothelial cells where it can activate RHOA (By similarity). Interacts with ASAP3 (phosphorylated form) (PubMed:22027826). Interacts (via SH2 domain) with PTPRH (phosphorylated form) (By similarity). Interacts with PTPRO (phosphorylated form) (By similarity). Interacts with PTPRB (phosphorylated form) (By similarity). Interacts (via SH3 domain 2) with PRR14 (via proline-rich region) (PubMed:27041574). Interacts with FCRL6 (tyrosine phosphorylated form) (PubMed:20933011). Interacts with RHEX (via tyrosine-phosphorylated form) (PubMed:25092874). Interacts with DENND2B (PubMed:29030480). Interacts with SPRY2 (PubMed:17974561). Interacts with LRRC8A (By similarity).SUBUNIT (Microbial infection) Interacts (via SH3 domain) with hepatitis E virus/HEV ORF3 protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus/HCV protein NS5A via its SH3 domains.SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL46.DOMAIN The SH3 domains mediate interaction with RALGPS1 and SHB.SIMILARITY Belongs to the GRB2/sem-5/DRK family.CAUTION Was shown to interact with ZDHHC19, leading to recruitment of STAT3. However, this study was later retracted. UniProt P62993-1 1 EQUAL 217 EQUAL Reactome Database ID Release 81 109797 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=109797 Reactome R-HSA-109797 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-109797.3 Reactome DB_ID: 2179409 1 GRB2:SOS1:HB-EGF:p-6Y-EGFR [plasma membrane] GRB2:SOS1:HB-EGF:p-6Y-EGFR Reactome DB_ID: 2179410 1 Reactome DB_ID: 109797 1 Reactome Database ID Release 81 2179409 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=2179409 Reactome R-HSA-2179409 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-2179409.1 Reactome Database ID Release 81 2179415 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=2179415 Reactome R-HSA-2179415 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-2179415.1 7527043 Pubmed 1994 Grb2/Ash binds directly to tyrosines 1068 and 1086 and indirectly to tyrosine 1148 of activated human epidermal growth factor receptors in intact cells Okutani, T Okabayashi, Y Kido, Y Sugimoto, Y Sakaguchi, K Matuoka, K Takenawa, T Kasuga, M J Biol Chem 269:31310-4 7518560 Pubmed 1994 Hierarchy of binding sites for Grb2 and Shc on the epidermal growth factor receptor Batzer, AG Rotin, D Urena, JM Skolnik, EY Schlessinger, J Mol Cell Biol 14:5192-201 SOS1-mediated nucleotide exchange of RAS (HB-EFG-initiated) SOS1-mediated nucleotide exchange of RAS (HB-EFG-initiated) SOS1 is the guanine nucleotide exchange factor (GEF) for RAS. SOS1 activates RAS nucleotide exchange from the inactive form (bound to GDP) to an active form (bound to GTP) (Chardin et al. 1993). Authored: Jassal, Bijay, Tripathi, S, 2012-04-04 Reviewed: D'Eustachio, P, 2012-04-23 Edited: Jassal, Bijay, Tripathi, S, 2012-04-04 Reactome DB_ID: 29438 1 GTP(4-) [ChEBI:37565] GTP(4-) GTP gtp guanosine 5'-triphosphate(4-) ChEBI 37565 Reactome DB_ID: 109796 1 p21 RAS:GDP [plasma membrane] p21 RAS:GDP Reactome DB_ID: 29420 1 GDP(3-) [ChEBI:58189] GDP(3-) guanosine 5'-diphosphate(3-) 5'-O-[(phosphonatooxy)phosphinato]guanosine guanosine 5'-diphosphate trianion GDP GDP trianion guanosine 5'-diphosphate ChEBI 58189 Converted from EntitySet in Reactome Reactome DB_ID: 9649715 1 mature p21 RAS [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity S-Farn-Me PalmS NRAS [plasma membrane] S-Farn-Me-2xPalmS HRAS [plasma membrane] S-Farn-Me-PalmS KRAS4A [plasma membrane] S-Farn-Me KRAS4B [plasma membrane] UniProt P01111 UniProt P01112 UniProt P01116-1 UniProt P01116-2 Reactome Database ID Release 81 109796 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=109796 Reactome R-HSA-109796 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-109796.2 Reactome DB_ID: 29420 1 Reactome DB_ID: 109783 1 p21 RAS:GTP [plasma membrane] p21 RAS:GTP Reactome DB_ID: 29438 1 Converted from EntitySet in Reactome Reactome DB_ID: 9649715 1 Reactome Database ID Release 81 109783 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=109783 Reactome R-HSA-109783 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-109783.2 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 2179409 GO 0005085 GO molecular function Reactome Database ID Release 81 2179400 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=2179400 Reactome Database ID Release 81 2179407 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=2179407 Reactome R-HSA-2179407 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-2179407.1 8493579 Pubmed 1993 Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2 Chardin, P Camonis, JH Gale, NW Van Aelst, L Schlessinger, J Wigler, Michael H Bar-Sagi, Dafna Science 260:1338-43 Reactome Database ID Release 81 2179392 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=2179392 Reactome R-HSA-2179392 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-2179392.1 20398727 Pubmed 2011 EGF receptor activation by GPCRs: an universal pathway reveals different versions Liebmann, C Mol Cell Endocrinol 331:222-31 16816139 Pubmed 2006 Cholecystokinin and gastrin receptors Dufresne, M Seva, C Fourmy, D Physiol Rev 86:805-47 2.7.11.1 ERK1/2/5 activate RSK1/2/3 ERK1/2/5 activate RSK1/2/3 The p90 ribosomal S6 kinases (RSK1-4) comprise a family of serine/threonine kinases that lie at the terminus of the ERK pathway. RSK family members are unusual among serine/threonine kinases in that they contain two distinct kinase domains, both of which are catalytically functional . The C-terminal kinase domain is believed to be involved in autophosphorylation, a critical step in RSK activation, whereas the N-terminal kinase domain, which is homologous to members of the AGC superfamily of kinases, is responsible for the phosphorylation of all known exogenous substrates of RSK.<br>RSKs can be activated by the ERKs (ERK1, 2, 5) in the cytoplasm as well as in the nucleus, they both have cytoplasmic and nuclear substrates, and they are able to move from nucleus to cytoplasm. Efficient RSK activation by ERKs requires its interaction through a docking site located near the RSK C terminus. The mechanism of RSK activation has been studied mainly with regard to ERK1 and ERK2. RSK activation leads to the phosphorylation of four essential residues Ser239, Ser381, Ser398, and Thr590, and two additional sites, Thr377 and Ser749 (the amino acid numbering refers to RSK1). ERK is thought to play at least two roles in RSK1 activation. First, activated ERK phosphorylates RSK1 on Thr590, and possibly on Thr377 and Ser381, and second, ERK brings RSK1 into close proximity to membrane-associated kinases that may phosphorylate RSK1 on Ser381 and Ser398.<br>Moreover, RSKs and ERK1/2 form a complex that transiently dissociates upon growth factor signalling. Complex dissociation requires phosphorylation of RSK1 serine 749, a growth factor regulated phosphorylation site located near the ERK docking site. Serine 749 is phosphorylated by the N-terminal kinase domain of RSK1 itself. ERK1/2 docking to RSK2 and RSK3 is also regulated in a similar way. The length of RSK activation following growth factor stimulation depends on the duration of the RSK/ERK complex, which, in turn, differs among the different RSK isoforms. RSK1 and RSK2 readily dissociate from ERK1/2 following growth factor stimulation stimulation, but RSK3 remains associated with active ERK1/2 longer, and also remains active longer than RSK1 and RSK2. <br> Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Edited: D'Eustachio, P, 2013-07-15 Edited: Matthews, L, 2013-07-15 Converted from EntitySet in Reactome Reactome DB_ID: 199858 1 nucleoplasm GO 0005654 Ribosomal protein S6 kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity RPS6KA3 [nucleoplasm] RPS6KA1 [nucleoplasm] RPS6KA2 [nucleoplasm] UniProt P51812 UniProt Q15418 UniProt Q15349 Reactome DB_ID: 29358 6 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Converted from EntitySet in Reactome Reactome DB_ID: 199849 1 Phospho-Ribosomal protein S6 kinase [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity p-4S,T359,T573-RPS6KA1 [nucleoplasm] p-4S,T356,T570-RPS6KA2 [nucleoplasm] p-4S,T231,T365-RPS6KA3 [nucleoplasm] Reactome DB_ID: 113582 6 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 199878 p-MAPK3/MAPK1/MAPK7 dimers [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0004674 GO molecular function Reactome Database ID Release 81 199864 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=199864 Reactome Database ID Release 81 198746 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=198746 Reactome R-HSA-198746 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-198746.3 16626623 Pubmed 2006 The MAP kinase ERK5 binds to and phosphorylates p90 RSK Ranganathan, A Pearson, GW Chrestensen, CA Sturgill, TW Cobb, MH Arch Biochem Biophys 449:8-16 12832467 Pubmed 2003 Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity Roux, PP Richards, SA Blenis, J Mol Cell Biol 23:4796-804 2.7.11.1 RSK1/2/3 phosphorylates CREB at Serine 133 RSK1/2/3 phosphorylates CREB at Serine 133 CREB is phosphorylated at Serine 133 by RSK1/2/3. Authored: Nasi, Sergio, Annibali, D, 2006-10-10 Reviewed: Greene, LA, 2007-11-08 15:39:37 Reactome DB_ID: 52777 1 UniProt:P16220 CREB1 CREB1 CREB1 FUNCTION Phosphorylation-dependent transcription factor that stimulates transcription upon binding to the DNA cAMP response element (CRE), a sequence present in many viral and cellular promoters. Transcription activation is enhanced by the TORC coactivators which act independently of Ser-119 phosphorylation. Involved in different cellular processes including the synchronization of circadian rhythmicity and the differentiation of adipose cells.SUBUNIT Interacts with PPRC1. Binds DNA as a dimer. This dimer is stabilized by magnesium ions. Interacts, through the bZIP domain, with the coactivators TORC1/CRTC1, TORC2/CRTC2 and TORC3/CRTC3. When phosphorylated on Ser-119, binds CREBBP (By similarity). Interacts with CREBL2; regulates CREB1 phosphorylation, stability and transcriptional activity (By similarity). Interacts (phosphorylated form) with TOX3. Interacts with ARRB1. Binds to HIPK2. Interacts with SGK1. Interacts with TSSK4; this interaction facilitates phosphorylation on Ser-119 (PubMed:15964553). Forms a complex with KMT2A and CREBBP (PubMed:23651431).SUBUNIT (Microbial infection) Interacts with hepatitis B virus/HBV protein X.SUBUNIT (Microbial infection) Interacts with HTLV-1 protein Tax.PTM Stimulated by phosphorylation. Phosphorylation of both Ser-119 and Ser-128 in the SCN regulates the activity of CREB and participates in circadian rhythm generation. Phosphorylation of Ser-119 allows CREBBP binding. In liver, phosphorylation is induced by fasting or glucagon in a circadian fashion (By similarity). CREBL2 positively regulates phosphorylation at Ser-119 thereby stimulating CREB1 transcriptional activity (By similarity). Phosphorylated upon calcium influx by CaMK4 and CaMK2 on Ser-119. CaMK4 is much more potent than CaMK2 in activating CREB. Phosphorylated by CaMK2 on Ser-128. Phosphorylation of Ser-128 blocks CREB-mediated transcription even when Ser-119 is phosphorylated. Phosphorylated by CaMK1 (By similarity). Phosphorylation of Ser-257 by HIPK2 in response to genotoxic stress promotes CREB1 activity, facilitating the recruitment of the coactivator CBP. Phosphorylated at Ser-119 by RPS6KA3, RPS6KA4 and RPS6KA5 in response to mitogenic or stress stimuli. Phosphorylated by TSSK4 on Ser-119 (PubMed:15964553).PTM Sumoylated with SUMO1. Sumoylation on Lys-290, but not on Lys-271, is required for nuclear localization of this protein. Sumoylation is enhanced under hypoxia, promoting nuclear localization and stabilization.DISEASE A CREB1 mutation has been found in a patient with multiple congenital anomalies consisting of agenesis of the corpus callosum, cerebellar hypoplasia, severe neonatal respiratory distress refractory to surfactant, thymus hypoplasia, and thyroid follicular hypoplasia.SIMILARITY Belongs to the bZIP family. UniProt P16220 1 EQUAL 341 EQUAL Reactome DB_ID: 29358 1 Reactome DB_ID: 111910 1 O-phospho-L-serine at 133 133 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 341 EQUAL Reactome DB_ID: 113582 1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 199849 Reactome Database ID Release 81 199892 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=199892 Reactome Database ID Release 81 199895 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=199895 Reactome R-HSA-199895 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-199895.1 9770464 Pubmed 1998 Rsk-2 activity is necessary for epidermal growth factor-induced phosphorylation of CREB protein and transcription of c-fos gene De Cesare, D Jacquot, S Hanauer, A Sassone-Corsi, P Proc Natl Acad Sci U S A 95:12202-7 Reactome Database ID Release 81 881907 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=881907 Reactome R-HSA-881907 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-881907.1 10413847 Pubmed 1999 [Receptors for cholecystokinin and gastrin] de Weerth, A Bläker, M von Schrenck, T Z Gastroenterol 37:389-401 17698287 Pubmed 2007 Role of gastrin peptides in carcinogenesis Grabowska, AM Watson, SA Cancer Lett 257:1-15 7491953 Pubmed 1995 Cholecystokinin receptors Wank, SA Am J Physiol 269:G628-46