REQUIREMENT OF PHOSPHATIDYLINOSITOL-3 KINASE FOR ACTIVATION OF JNK SAPKS BY PDGF/

The molecular mechanism by which cell surface receptors stimulate the serine/threonine kinase activity of c-Jun N-terminal kinases (JNKs) wa s investigated using a transient cotransfection experiments in COS-7 c ells, Our data demonstrate that JNK activity is potently induced by pl atelet derived growth factor (PDGF) upon expression of beta PDGFR wild type (beta RWT). However, PDGF failed to mediate JNK activation in ce lls expressing beta PDGFR mutant lacking the binding site for phosphat idylinositol-3 (PI-3) kinase but not for phospholipase C gamma (PLC ga mma) or Syp. Consistent with this result, a PI-3 kinase inhibitor, wor tmannin inhibited activation of JNK by PDGF. Furthermore, overexpressi on of P110 the catalytic domain of PI-3 kinase was sufficient for acti vation of JNKs which could be efficiently inhibited by dominant negati ve forms of Pas, Pac but not of RhoA or Cdc42. Taken together all of t hese findings suggest that activation of JNK by PDGF involves receptor association with PI-3 kinase activity, which in turn acts on a ras- a nd rac-dependent pathway. (C) 1997 Academic Press.