Gastrin, CCK, signaling, and cancer

Gastrin, produced by G cells in the gastric antrum, has been identified as the circulating hormone responsible for stimulation of acid secretion from the parietal cell. Gastrin also acts as a potent cell-growth factor that ha s been implicated in a variety of normal and abnormal biological processes including maintenance of the gastric mucosa, proliferation of enterochromaf fin-like cells, and neoplastic transformation, Here, we review the models u sed to study the effects of gastrin on cell proliferation in vivo and in vi tro with respect to mechanisms by which this hormone might influence normal and cancerous cell growth. Specifically, human and animal models of hyperg astrinemia and hypogastrinemia have been described in vivo, and several cel ls that express cholecystokinin (CCK)(B)/gastrin receptors have been used f or analysis of intracellular signaling pathways initiated by biologically a ctive amidated gastrins. The binding of gastrin or CCK to their common cogn ate receptor triggers the activation of multiple signal transduction pathwa ys that relay the mitogenic signal to the nucleus and promote cell prolifer ation. A rapid increase in the synthesis of lipid-derived second messengers with subsequent activation of protein phosphorylation cascades, including mitogen-activated protein kinase, is an important early response to these s ignaling peptides, Gastrin and CCK also induce rapid Rho-dependent actin re modeling and coordinate tyrosine phosphorylation of cellular proteins inclu ding the non-receptor tyrosine kinases p125(fak) and Src and the adaptor pr oteins p130(cas) and paxillin, This article reviews recent advances in defi ning the role of gastrin and CCK in the control of cell proliferation in no rmal and cancer cells and in dissecting the signal transduction pathways th at mediate the proliferative responses induced by these hormonal GI peptide s in a variety of normal and cancer cell model systems.