RECEPTOR TYROSINE KINASE STIMULATES CELL-MATRIX ADHESION BY PHOSPHATIDYLINOSITOL-3 KINASE AND PHOSPHOLIPASE C-GAMMA-1 PATHWAYS

Receptor tyrosine kinases are known to be important in growth and diff erentiation, We have recently found that c-kit, the tyrosine kinase re ceptor for steel factor, also regulates cell-matrix adhesion. Because Steel factor helps regulate cell migration and localization, this may be an important biologic function. Integrin adhesiveness is regulated within minutes by c-kit. The signaling pathways for tyrosine kinase st imulation of integrin adhesiveness and their relation to pathways that regulate growth and differentiation over much longer time periods rem ain uncharacterized, We have studied the effector pathways by which re ceptor tyrosine kinases regulate cell-matrix adhesion using wild-type and mutant forms of the platelet-derived growth factor (PDGF) receptor , which is closely related to c-kit. The PDGF receptor expressed in ma st cells is as potent as c-kif in stimulating adhesion to fibronectin. We show that induction of adhesion is regulated through two independe nt pathways of phosphatidylinositol 3 kinase (Pl3K) and phospholipase C-gamma 1 (PLC gamma)-protein kinase C by elimination of autophosphory lation sites required for activation of Pl3K and PLC gamma or in combi nation with downregulation of protein kinase C or wortmannin, By contr ast, a receptor mutated in both the Pl3K and PLC gamma association sit es can still stimulate mast cell growth, indicating a crucial role of these effector molecules in regulating adhesion rather than cell growt h, (C) 1995 by The American Society of Hematology.