PHOSPHORYLATION OF P130(CAS) BY ANGIOTENSIN-II IS DEPENDENT ON C-SRC,INTRACELLULAR CA2-KINASE-C(, AND PROTEIN)

p130(Cas) is a signaling molecule that was initially found to be tyros ine-phosphorylated in v-Crk and v-Src transformed cells. We characteri zed the regulation of p130(Cas) tyrosine phosphorylation in vascular s mooth muscle cells by angiotensin II (Ang II). This ligand induced a t ransient increase in p130c'''' tyrosine phosphorylation, which was sen sitive to the actin polymerization inhibitor cytochalasin D and to the intracellular Ca2+ chelator BAPTA-AM but not the Ca2+ channel blocker verapamil. The Ang II-induced tyrosine phosphorylation of p130(Cas) w as also dependent on an active Src family tyrosine kinase, since it co uld be blocked by the Src kinase inhibitors geldanamycin and PP1, Ang II treatment resulted in the ability of p130(Cas) to bind at least 11 different phosphate-containing, proteins, Analysis of these proteins r evealed that protein kinase C alpha and the cell adhesion signaling mo lecule pp120 formed temporal associations with p130(Cas) in response t o Ang II. c-Src was found to associate with p130(Cas) in a manner that was independent of Ang II treatment. Inhibition of protein kinase C b y either calphostin C or phorbol 12-myristate 13-acetate downregulatio n inhibited the Ang II-induced tyrosine phosphorylation of p130(Cas), These results are the first to demonstrate that the tyrosine phosphory lation of p130(Cas) by Ang II is transduced by the Src, intracellular Ca2+, protein kinase C signaling pathway.