Gastrin-induced DNA synthesis requires p38-MAPK activation via PKC/Ca2+ and Src-dependent mechanisms

We present evidence that gastrin, binding to a G protein-coupled receptor, activates the p38-nitrogen-activated protein kinase (MAPK) pathway. Blockage of protein kinase C (PKC) by GF109203X, depletion of intracellular calcium by thapsigargin or inhibition of Src family kinases by PP2 prevented p38-MAPK activation and the Src kinase activity stimulated by gastrin, Inhibition of the PI 3-kinase by wortmannin or LY294002 did not affect these responses. In addition, the p38-MAPK inhibitor, SB203580, repressed gastrin-induced [H-3]thymidine incorporation, indicating a major role of p38-MAPK in the growth-promoting effect of gastrin, Our results demonstrate that gastrin-induced DNA synthesis requires p38-MAPK activation through mechanisms that involve calcium mobilization, PKC and Src family kinases, (C) 2001 Published by Elsevier Science B.V, on behalf of tbe Federation of European Biochemical Societies.