Treatment of Swiss 3T3 cells with bombesin rapidly induced tyrosine phosphorylation of the p130 Crk-associated substrate (p130 cas ). Vasopressin, endothelin, bradykinin, lysophosphatidic acid, sphingosylphosphorylcholine, and phorbol 12,13-dibutyrate also stimulated p130 cas tyrosine phosphorylation. Bombesin-induced p130 cas tyrosine phosphorylation could be dissociated from both protein kinase C activation and Ca 2؉ mobilization from intracellular stores. In contrast, cytochalasin D, which

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... srupts the network of actin microfilaments, completely prevented tyrosine phosphorylation of p130 cas by bombesin. Platelet-derived growth factor, at low concentrations (1-5 ng/ml), also induced tyrosine phosphorylation of p130 cas via a pathway that depended on the integrity of the actin cytoskeleton. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 prevented tyrosine phosphorylation of p130 cas in response to platelet-derived growth factor but not in response to neuropeptides, lysophosphatidic acid, sphingosylphosphorylcholine, or phorbol 12,13-dibutyrate. All agonists that induced p130 cas tyrosine phosphorylation also promoted the formation of a p130 cas ⅐Crk complex in intact Swiss 3T3 cells. Thus, our results identified distinct signal transduction pathways that lead to tyrosine phosphorylation of p130 cas in the same cells and suggest that p130 cas could play a role in mitogen-mediated signal transduction.