A switch from p130Cas/Crk to Gab1/Crk signaling correlates with anchorage independent growth and JNK activation in cells transformed by the Met receptor oncoprotein

Cell transformation is associated with anchorage independent growth and mor phological changes characterized by reduced adhesion and spreading, The mol ecular signals that control these events are poorly understood. The Met rec eptor tyrosine kinase is deregulated in human tumors and an oncogenic deriv ative of this receptor transforms cells. In this paper we demonstrate that fibroblasts transformed by the Met oncoprotein display decreased cell sprea ding consistent with the loss of actin stress fibers and vinculin staining focal adhesions. In contrast to control cells, focal adhesion kinase, p130C as and paxillin are weakly or not detectably tyrosine phosphorylated in Met transformed cells. Moreover, although paxillin and p130Cas associate with the Crk adapter protein in control cells, they fail to associate with Crk i n Met transformed cells, yet these cells are motile and capable of wound cl osure to the same extent as control cells. In Met transformed cells, Crk pr edominantly associates with the CM and Gab1 docking proteins in a tyrosine phosphorylation dependent manner. The coupling of Gab1, but not Cbl, with C rk is retained in cells grown in suspension and enhances JNK activation. We propose that the loss of adhesion dependent signals required for cell cycl e progression is compensated through Met induced Gab1/Crk signals.