Gastrin signaling (WP4659)

Homo sapiens

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. Visit: http://www.netpath.org/netslim/Gastrin_pathway.html

Authors

Yashwanth Subbannayya , Kristina Hanspers , Denise Slenter , Eric Weitz , and Egon Willighagen

Activity

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Organisms

Homo sapiens

Communities

Annotations

Pathway Ontology

hormone signaling pathway peptide and protein hormone signaling pathway

Cell Type Ontology

gastrin secreting cell

Participants

Label Type Compact URI Comment
RHOD GeneProduct ncbigene:29984
RHOB GeneProduct ncbigene:388
CDKN1B GeneProduct ncbigene:1027
RHOA GeneProduct ncbigene:387
SOS1 GeneProduct ncbigene:6654
PIK3R1 GeneProduct ncbigene:5295
PIK3CA GeneProduct ncbigene:5290
PIK3R3 GeneProduct ncbigene:8503
PIK3R2 GeneProduct ncbigene:5296
PPARG GeneProduct ncbigene:5468
ELK1 GeneProduct ncbigene:2002
MAPK1 GeneProduct ncbigene:5594
ROCK1 GeneProduct ncbigene:6093
SP1 GeneProduct ncbigene:6667
PTK2 GeneProduct ncbigene:5747
MAPK3 GeneProduct ncbigene:5595
EGR1 GeneProduct ncbigene:1958
PXN GeneProduct ncbigene:5829
CDC42 GeneProduct ncbigene:998
RAC1 GeneProduct ncbigene:5879
PRKCA GeneProduct ncbigene:5578
MAP2K1 GeneProduct ncbigene:5604
LAMTOR3 GeneProduct ncbigene:8649
PAK1 GeneProduct ncbigene:5058
AKT1 GeneProduct ncbigene:207
JAK2 GeneProduct ncbigene:3717
STAT3 GeneProduct ncbigene:6774
CTNNB1 GeneProduct ncbigene:1499
TCF4 GeneProduct ncbigene:6925
PLCG1 GeneProduct ncbigene:5335
RPS6KB1 GeneProduct ncbigene:6198
RPS6 GeneProduct ncbigene:6194
ARHGEF28 GeneProduct ncbigene:64283
CD44 GeneProduct ncbigene:960
NFKBIA GeneProduct ncbigene:4792
NFKB1 GeneProduct ncbigene:4790
RELA GeneProduct ncbigene:5970
CHUK GeneProduct ncbigene:1147
IKBKB GeneProduct ncbigene:3551
GSK3B GeneProduct ncbigene:2932
MAPK8 GeneProduct ncbigene:5599
MAP3K11 GeneProduct ncbigene:4296
JUN GeneProduct ncbigene:3725
BIRC5 GeneProduct ncbigene:332
BCL2L1 GeneProduct ncbigene:598
VEGFA GeneProduct ncbigene:7422
CASP3 GeneProduct ncbigene:836
CREB1 GeneProduct ncbigene:1385
RAF1 GeneProduct ncbigene:5894
BIRC3 GeneProduct ncbigene:330
GNAQ GeneProduct ncbigene:2776
SRC GeneProduct ncbigene:6714
IRS1 GeneProduct ncbigene:3667
SHC1 GeneProduct ncbigene:6464
PTPN11 GeneProduct ncbigene:5781
SERPINE1 GeneProduct ncbigene:5054
CHGA GeneProduct ncbigene:1113
BIRC2 GeneProduct ncbigene:329
JAG1 GeneProduct ncbigene:182
MMP7 GeneProduct ncbigene:4316
MYC GeneProduct ncbigene:4609
IL2 GeneProduct ncbigene:3558
ITGB1 GeneProduct ncbigene:3688
PRKD1 GeneProduct ncbigene:5587
PRKD2 GeneProduct ncbigene:25865
FOXO3 GeneProduct ncbigene:2309
FOXO1 GeneProduct ncbigene:2308
PRKCD GeneProduct ncbigene:5580
MAPK14 GeneProduct ncbigene:1432
MAPK9 GeneProduct ncbigene:5601
GRB2 GeneProduct ncbigene:2885
BCAR1 GeneProduct ncbigene:9564
CRK GeneProduct ncbigene:1398
PRKCH GeneProduct ncbigene:5583
PRKCE GeneProduct ncbigene:5581
PRKACA GeneProduct ncbigene:5566
NOS3 GeneProduct ncbigene:5058
CDKN1A GeneProduct ncbigene:1026
CDKN2A GeneProduct ncbigene:1029
KAT5 GeneProduct ncbigene:10524
HDAC7 GeneProduct ncbigene:51564
KLF4 GeneProduct ncbigene:9314
SERPINB2 GeneProduct ncbigene:5055
TFF2 GeneProduct ncbigene:7032
CCND1 GeneProduct ncbigene:595
HDC GeneProduct ncbigene:3067
ATF2 GeneProduct ncbigene:1386
MEF2B GeneProduct ncbigene:100271849
MEF2C GeneProduct ncbigene:4208
MEF2D GeneProduct ncbigene:4209
HRAS GeneProduct ncbigene:3265
KRAS GeneProduct ncbigene:3845
EIF4EBP1 GeneProduct ncbigene:1978
BAD GeneProduct ncbigene:572
YES1 GeneProduct ncbigene:7525
FYN GeneProduct ncbigene:2534
PRKCQ GeneProduct ncbigene:5588
FOS GeneProduct ncbigene:2353
PTGS2 GeneProduct ncbigene:5743
ANXA2 GeneProduct ncbigene:302
ARRB1 GeneProduct ncbigene:408
ARRB2 GeneProduct ncbigene:409
BMP2 GeneProduct ncbigene:650
IL8 GeneProduct ncbigene:3576
GAST GeneProduct ncbigene:2520
CCKBR GeneProduct ncbigene:887
CDH1 GeneProduct ncbigene:999
EGFR GeneProduct ncbigene:1956
SLC9A3 GeneProduct ncbigene:6550
SLC9A1 GeneProduct ncbigene:6548
KIT GeneProduct ncbigene:3815
TJP1 GeneProduct ncbigene:7082
CLDN1 GeneProduct ncbigene:9076
MTOR Protein ncbigene:2475
ELAVL1 Protein ncbigene:1994
Protein Protein ncbigene:5894
Gast-17-Gly Protein ncbigene:2520
Gast-34-Gly Protein ncbigene:2520
Gast-17 Protein ncbigene:2520
Gast-34 Protein ncbigene:2520
GAST Protein ncbigene:2520
Progastrin Protein ncbigene:2520

References

  1. A network map of the gastrin signaling pathway. Subbannayya Y, Anuja K, Advani J, Ojha UK, Nanjappa V, George B, et al. J Cell Commun Signal. 2014 Jun;8(2):165–70. PubMed Europe PMC Scholia