GASTRIN INDUCES TYROSINE PHOSPHORYLATION OF SHC PROTEINS AND THEIR ASSOCIATION WITH THE GRB2 SOS COMPLEX/

Gastrin/CCKB G protein-coupled receptors have been shown to mediate pr oliferative effects of their endogenous ligands, In the present study, we examined the signal transduction mechanisms linked to the G/CCK, r eceptor occupancy. We report here that gastrin stimulates MAP kinase a ctivation in a dose- and time-dependent manner, a pathway known to pla y a key role in cell proliferation. We also characterized the molecula r events, upstream of p21-Ras, that mag link the MAP kinase pathway to G/CCKB, receptors. Gastrin induced a rapid and transient increase in tyrosine phosphorylation of several proteins including the 2 isoforms (46 and 52 kDa) of the adaptor protein She. Phosphorylated She subsequ ently associated with a complex that includes Grb2 and the p21-Ras act ivator, Sos. Our results also indicate that Sos becomes phosphorylated in response to gastrin as shown by a reduction in electrophoretic mob ility of the protein. Tyrosine phosphorylation of She and subsequent c omplex formation with Grb2 and Sos appear to be a common mechanism by which tyrosine kinase receptors and the G/CCKB G protein-coupled recep tor stimulate the Pas-dependent MAP kinase pathway.