Involvement of phosphatidylinositol 3-kinase and mitogen-activated proteinkinases in glycine-extended gastrin-induced dissociation and migration of gastric epithelial cells

The various molecular forms of gastrin can act as promoters of proliferatio n and differentiation in different regions of the gastrointestinal tract. W e report a novel stimulatory effect of glycine-extended gastrin(17) only on cell/cell dissociation and cell migration in a nontumorigenic mouse gastri c epithelial cell line (IMGE-5). In contrast, both amidated and glycine-ext ended gastrin17 stimulated proliferation of IMGE-5 cells via distinct recep tors. Glycine-extended gastrin(17)-induced dissociation preceded migration and was blocked by selective inhibitors of phosphatidylinositol 3-kinase (P 13-kinase) but did not require mitogen-activated protein (MAP) kinase activ ation. Furthermore, glycine-extended gastrin(17) induced a P13-kinase-media ted tyrosine phosphorylation of the adherens junction protein beta -catenin , partial dissociation of the complex between beta -catenin and the transme mbrane protein E-cadherin, and delocalization of beta -catenin into the cyt oplasm. Long lasting activation of MAP kinases by glycine-extended gastrin1 7 was specifically required for the migratory response, in contrast to the involvement of a rapid and transient MAP kinase activation in the prolifera tive response to both amidated and glycine-extended gastrin(17). Therefore, the time course of MAP kinase activation appears to be a critical determin ant of the biological effects mediated by this pathway. Together with the i nvolvement of P13-kinase in the dissociation of adherens junctions, long te rm activation of MAP kinases seems responsible for the selectivity of this novel effect of G(17)-Gly on the adhesion and migration of gastric epitheli al cells.