Gastrin Signaling Pathway (Homo sapiens)

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GastrinsRHODGTPRHOBGTPCDKN1BS10RHOAGTPSOS1PIK3R1Y467PIK3CAPIK3R3Y1991PIK3R2Y464PIP3Gastrin signaling pathwayCYProliferationin AGS-GR cellsand ColorectalmucosaPPARGS84ELK1S383MAPK1Y187T185ROCK1SP1PPTK2Y397Y577Y576MAPK3Y204T202EGR1PPXNY31CDC42GTPRAC1GTPPRKCAS657MAP2K1PLAMTOR3PAK1PAKT1S473JAK2PSTAT3S727Y705STAT3S727Y705CTNNB1S45T41TCF4PIP2PLCG1PIP3DAGMTORRPS6KB1PRPS6S236S235Internalizationand reduction insodium transportCTNNB1ARHGEF28Increased focal adhesionin DLD-1 cellsCD44NFKBIAUbNFKB1RELAS276CHUKIKBKBDissociationNFKB1RELAS276Regulation ofcell migrationand invasionGSK3BS9DissociationMAPK8Y185T183MAP3K11JUNPJUNPMigration of gastriccancer cellsBIRC5BCL2L1VEGFAAnti-apoptosis inQhERT Barrett's oesophageal, OE33and BIC-1 OAC cellsCASP3Anti-apoptosisCREB1S133RAF1Anti-apoptosisBIRC3GNAQSRCY419IRS1PSHC1PPTPN11SERPINE1CHGABIRC2JAG1MMP7MYCIL2Decreasein activityITGB1PPRKD1PRKD2S876S706S710PRKD1PRKD2S876S710S706FOXO3PFOXO1PPRKCDPMAPK14Y182T180MAPK9T183Y185GRB2BCAR1PCRKPRKCHPRKCEcAMPPRKACAT198NOS3S1177Production ofNitric Oxide inporcine coronaryendothelial cellsDissociationDissociation ofadherens junctionsin gastrointestinalepithelial cellsPAK1PCDKN1AS146G1 cell cyclearrest inpancreaticstellate cellsCollagensynthesisin pancreaticstellate cellsCDKN2ACell proliferationand migration KAT5HDAC7KLF4ProstaglandinsynthesisELAVL1ELAVL1NUCYNUCYNUCYNUCYNUCYNUCYNUSERPINB2TFF2CCND1HDCATF2PMEF2BMEF2CMEF2DHRASGTPKRASGTPProteinmRNALigandAuto catalysisTranslocationPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionUbiquitinationInduced catalysisProtein-protein interactionLEGENDPhosphorylationProteinNucleusCytoplasmCYNUInduced activationProteinProtein-protein dissociationReceptorEIF4EBP1PBADPYES1PFYNPPRKCQPFOSGast-17-GlyGast-34-GlyGast-17Gast-34GASTProgastrinInhibitionHistamine synthesisand secretion in ECL cellsSmall moleculePTGS2ANXA2GASTPMCYPlasma membranePMARRB1ARRB2Colonic stem cellproliferationBMP2IL8Clathrin-mediatedGASTTFF2Proliferationin Colorectalmucosa gastriccancer cellsMAPK1T185Y187MAPK14MAPK3Y204Y182T180T202CYNUCCKBRCDH1EGFRY1172SLC9A3S555SLC9A1KITY703Y721ANXA2GASTNucleusCytoplasmTJP1Dissociationof tight junction ingastrointestinal epithelial cellsCLDN1Plasma Membrane


Description

Gastrin is a peptide hormone which is involved in the process of gastric acid secretion. Gastrin release is induced by the gastrin-releasing peptide, a neurotransmitter acting on its basolateral receptor in G-cells. Gastrin is then translocated to the oxyntic mucosa in an endocrine manner where it binds to its receptor CCKBR in parietal and enterochromaffin-like (ECL) cells. This interaction stimulates secretion of gastric acid by parietal cells and release of histamine by ECL cells. Histamine reaches parietal cells through paracrine diffusion where it binds H2 receptors and induces gastric acid secretion. Gastrin has been reported to stimulate proliferation of gastric mucosal cells,maturation of parietal cells and enterochromaffin-like (ECL) cells, and promote islet differentiation in the pancreas. Gastrin is also known to stimulate the proliferation, invasion, and migration of cancer cells. Produced as preprogastrin of 101 amino acids by the human G-cells of the antrum of stomach, it is sequentially cleaved to first yield progastrin and then 35-amino acid gastrin-34-Gly or an 18-amino acid gastrin-17-Gly that are often amidated.

CCKAR and CCKBR cholecystokinin receptors belonging to the family of G-protein coupled receptors, are the best characterized receptors of Gastrin. CCKBR has high affinity for gastrin and their carboxyl amidated analogues, while the CCKAR has been reported to have negligible affinity. Gq-alpha had been the major identified G-alpha subunit involved in gastrin signaling. Gastrin induces the activation of Gq-alpha and regulates the levels of IP3 and DAG through PLC-gamma1 mediated hydrolysis of PIP2. SRC has also been shown to be involved in this regulation. SRC kinase is also involved in the activation of classical RAS/MEK/ERK and PI3K/AKT pathways through IRS1-mediated recruitment of GRB2/SHC1/SOS complex and regulatory subunits of PI3Ks, respectively. PI3K pathway activation by SRC also involves the formation of SRC-FAK complexes. Gastrin induced MEK/ERK pathway is also reported to be mediated through PKCs. Gastrins have also been reported to regulate the activation of Rho, Rac and Cdc42 pathways. Recently, Liu and Jose 2013 have reported the regulation of MTOR and sodium-hydrogen exchanger 3 activities through a PI3K/PKC-dependent but AKT-independent pathway. Both p38MAPK and JNKs are also reported to be involved in gastrin signaling. PKAs as well as PKCs are involved in the regulation of p38MAPK activation whereas JNK activation has been shown to be mediated by MAP3K11 (MLK3). Gastrin induces the activation of eNOS and thereby nitric oxide production in ERK1/2, AKT, and p38MAPK dependent manner. Another major pathway involved in gastrin induced cell proliferation and migration is the beta-catenin/TCF-4 pathway. JAK-STAT pathway has also been shown to be involved in gastrin signaling. Interestingly, JAK2 activation has been identified to be also involved in activation of PI3K pathway.

Apart from CCKAR and CCKBR, recently gastrin has also been shown to bind to Annexin A2 to mediate their effects. Thus far, gastrin induced activation of NFKBs, ERKs and p38MAPK have been reported to be mediated by both CCK receptor(s) as well as Annexin A2 in multiple cells/cell types.

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Bibliography

  1. Subbannayya Y, Anuja K, Advani J, Ojha UK, Nanjappa V, George B, Sonawane A, Kumar RV, Ramaswamy G, Pandey A, Somani BL, Raju R; ''A network map of the gastrin signaling pathway.''; J Cell Commun Signal, 2014 PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
107967view09:32, 18 November 2019SubbannayyaPostional adjustment of MAP2K1 to unhide
107965view09:31, 18 November 2019SubbannayyaGrouped proteins including PI3K, RHO and RAC1-CDC42 to connect unconnected arros
106038view11:56, 16 August 2019DeSlOntology Term : 'peptide and protein hormone signaling pathway' added !
105422view16:37, 7 August 2019DeSlOntology Term : 'gastrin secreting cell' added !
105204view20:00, 19 July 2019KhanspersOntology Term : 'hormone signaling pathway' added !
105021view09:40, 28 June 2019SubbannayyaUpdated complexes
105020view09:34, 28 June 2019SubbannayyaDeleted module names, changed legend position
105019view09:24, 28 June 2019SubbannayyaAdded literature support for pathway
105018view09:20, 28 June 2019SubbannayyaNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
AKT1GeneProduct207 (Entrez Gene)
ANXA2GeneProduct302 (Entrez Gene)
ARHGEF28GeneProduct64283 (Entrez Gene)
ARRB1GeneProduct408 (Entrez Gene)
ARRB2GeneProduct409 (Entrez Gene)
ATF2GeneProduct1386 (Entrez Gene)
BADGeneProduct572 (Entrez Gene)
BCAR1GeneProduct9564 (Entrez Gene)
BCL2L1GeneProduct598 (Entrez Gene)
BIRC2GeneProduct329 (Entrez Gene)
BIRC3GeneProduct330 (Entrez Gene)
BIRC5GeneProduct332 (Entrez Gene)
BMP2GeneProduct650 (Entrez Gene)
CASP3GeneProduct836 (Entrez Gene)
CCKBRGeneProduct887 (Entrez Gene)
CCND1GeneProduct595 (Entrez Gene)
CD44GeneProduct960 (Entrez Gene)
CDC42GeneProduct998 (Entrez Gene)
CDH1GeneProduct999 (Entrez Gene)
CDKN1AGeneProduct1026 (Entrez Gene)
CDKN1BGeneProduct1027 (Entrez Gene)
CDKN2AGeneProduct1029 (Entrez Gene)
CHGAGeneProduct1113 (Entrez Gene)
CHUKGeneProduct1147 (Entrez Gene)
CLDN1GeneProduct9076 (Entrez Gene)
CREB1GeneProduct1385 (Entrez Gene)
CRKGeneProduct1398 (Entrez Gene)
CTNNB1GeneProduct1499 (Entrez Gene)
EGFRGeneProduct1956 (Entrez Gene)
EGR1GeneProduct1958 (Entrez Gene)
EIF4EBP1GeneProduct1978 (Entrez Gene)
ELAVL1Protein1994 (Entrez Gene)
ELK1GeneProduct2002 (Entrez Gene)
FOSGeneProduct2353 (Entrez Gene)
FOXO1GeneProduct2308 (Entrez Gene)
FOXO3GeneProduct2309 (Entrez Gene)
FYNGeneProduct2534 (Entrez Gene)
GASTProtein2520 (Entrez Gene)
GNAQGeneProduct2776 (Entrez Gene)
GRB2GeneProduct2885 (Entrez Gene)
GSK3BGeneProduct2932 (Entrez Gene)
Gast-17-GlyProtein2520 (Entrez Gene)
Gast-17Protein2520 (Entrez Gene)
Gast-34-GlyProtein2520 (Entrez Gene)
Gast-34Protein2520 (Entrez Gene)
HDAC7GeneProduct51564 (Entrez Gene)
HDCGeneProduct3067 (Entrez Gene)
HRASGeneProduct3265 (Entrez Gene)
IKBKBGeneProduct3551 (Entrez Gene)
IL2GeneProduct3558 (Entrez Gene)
IL8GeneProduct3576 (Entrez Gene)
IRS1GeneProduct3667 (Entrez Gene)
ITGB1GeneProduct3688 (Entrez Gene)
JAG1GeneProduct182 (Entrez Gene)
JAK2GeneProduct3717 (Entrez Gene)
JUNGeneProduct3725 (Entrez Gene)
KAT5GeneProduct10524 (Entrez Gene)
KITGeneProduct3815 (Entrez Gene)
KLF4GeneProduct9314 (Entrez Gene)
KRASGeneProduct3845 (Entrez Gene)
LAMTOR3GeneProduct8649 (Entrez Gene)
MAP2K1GeneProduct5604 (Entrez Gene)
MAP3K11GeneProduct4296 (Entrez Gene)
MAPK14GeneProduct1432 (Entrez Gene)
MAPK1GeneProduct5594 (Entrez Gene)
MAPK3GeneProduct5595 (Entrez Gene)
MAPK8GeneProduct5599 (Entrez Gene)
MAPK9GeneProduct5601 (Entrez Gene)
MEF2BGeneProduct100271849 (Entrez Gene)
MEF2CGeneProduct4208 (Entrez Gene)
MEF2DGeneProduct4209 (Entrez Gene)
MMP7GeneProduct4316 (Entrez Gene)
MTORProtein2475 (Entrez Gene)
MYCGeneProduct4609 (Entrez Gene)
NFKB1GeneProduct4790 (Entrez Gene)
NFKBIAGeneProduct4792 (Entrez Gene)
NOS3GeneProduct5058 (Entrez Gene)
PAK1GeneProduct5058 (Entrez Gene)
PIK3CAGeneProduct5290 (Entrez Gene)
PIK3R1GeneProduct5295 (Entrez Gene)
PIK3R2GeneProduct5296 (Entrez Gene)
PIK3R3GeneProduct8503 (Entrez Gene)
PLCG1GeneProduct5335 (Entrez Gene)
PPARGGeneProduct5468 (Entrez Gene)
PRKACAGeneProduct5566 (Entrez Gene)
PRKCAGeneProduct5578 (Entrez Gene)
PRKCDGeneProduct5580 (Entrez Gene)
PRKCEGeneProduct5581 (Entrez Gene)
PRKCHGeneProduct5583 (Entrez Gene)
PRKCQGeneProduct5588 (Entrez Gene)
PRKD1GeneProduct5587 (Entrez Gene)
PRKD2GeneProduct25865 (Entrez Gene)
PTGS2GeneProduct5743 (Entrez Gene)
PTK2GeneProduct5747 (Entrez Gene)
PTPN11GeneProduct5781 (Entrez Gene)
PXNGeneProduct5829 (Entrez Gene)
ProgastrinProtein2520 (Entrez Gene)
ProteinProtein5894 (Entrez Gene)
RAC1GeneProduct5879 (Entrez Gene)
RAF1GeneProduct5894 (Entrez Gene)
RELAGeneProduct5970 (Entrez Gene)
RHOAGeneProduct387 (Entrez Gene)
RHOBGeneProduct388 (Entrez Gene)
RHODGeneProduct29984 (Entrez Gene)
ROCK1GeneProduct6093 (Entrez Gene)
RPS6GeneProduct6194 (Entrez Gene)
RPS6KB1GeneProduct6198 (Entrez Gene)
SERPINB2GeneProduct5055 (Entrez Gene)
SERPINE1GeneProduct5054 (Entrez Gene)
SHC1GeneProduct6464 (Entrez Gene)
SLC9A1GeneProduct6548 (Entrez Gene)
SLC9A3GeneProduct6550 (Entrez Gene)
SOS1GeneProduct6654 (Entrez Gene)
SP1GeneProduct6667 (Entrez Gene)
SRCGeneProduct6714 (Entrez Gene)
STAT3GeneProduct6774 (Entrez Gene)
TCF4GeneProduct6925 (Entrez Gene)
TFF2GeneProduct7032 (Entrez Gene)
TJP1GeneProduct7082 (Entrez Gene)
VEGFAGeneProduct7422 (Entrez Gene)
YES1GeneProduct7525 (Entrez Gene)

Annotated Interactions

No annotated interactions

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