Cholecystokinin/Gastrin-mediated Signaling

Gastrointestinal peptides, including gastrin and cholecystokinin (CCK), are a structurally diverse group of molecular messengers that function in a rich network of information exchange systems throughout the organism. Gastrin is a circulating hormone responsible for stimulation of acid secretion from the parietal cell. Gastrin also acts as a potent cell-growth factor that has been implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of ECL, and neoplastic transformation. The binding of gastrin or CCK to their common cognate receptor triggers the activation of multiple signal transduction pathways that relay the mitogenic signal to the nucleus and promote cell proliferation.Gastrin, CCK, and CCK-related peptides exert their effects by binding to specific GPCR subtypes. The CCKBR/gastrin receptor binds gastrin and CCK with similar affinity, whereas the CCKAR exhibits a 500-fold higher affinity for CCK than for gastrin. One of the earliest events to occur after the binding of many gastrointestinal peptides agonists to their GPCRs is the activation of G-αq. This results in the stimulation of PLC-β, which catalyzes the hydrolysis of PIP2 in the plasma membrane to produce two second messengers: IP3 and DAG. IP3 triggers the release of Ca2+ from internal stores. DAG directly activates the isoforms of PKC which stimulates PYK2. In epithelial cells a likely chain of events is gastrin-induced (PLC-dependent) PKC activation and Ca2+ mobilization, PYK2-mediated stimulation of c-Src activation, and MAPK activation via tyrosine phosphorylation of adaptor proteins including SHC, the adaptor protein GRB2 and the guanine nucleotide release factor SOS, which binds to tyrosine kinase receptors and promotes the accumulation of p21Ras-GTP. In addition to the Gαq proteins, G-α12/13 are also activated by gastrin and CCK. This stimulates Rho-dependent actin stress fiber formation, focal adhesion assembly, and tyrosine phosphorylation of focal adhesion proteins.MAPK signal transduction pathways constitute one of the major mechanisms by which extracellular stimuli by these agonists are converted into specific nuclear responses. Several families of MAPKs including ERK1/2 are involved. Following MAPK activation, several other transcription factors are up-regulated, including Elk1, ATF2, c-Fos, c-Jun, MEF2 and AP-1. Another potential pathway is the transactivation of the EGFR by GPCR agonists, which also leads to p21Ras-dependent MAPK activation in a variety of cell types. Gastrin promotes the synthesis and processing of HB-EGF and induces tyrosine phosphorylation of EGFR.Biologically active amidated gastrins act as potent cellular growth factors that are implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of pancreatic, gastric, colonic, and small cell lung tumors, and neoplastic transformation.