Requirement of Phosphatidylinositol-3 Kinase for Activation of JNK/SAPKs by PDGF (original) (raw)

1997, Biochemical and Biophysical Research Communications

pholipase A2, p90 Rsk and nuclear proteins such as the The molecular mechanism by which cell surface reternary complex factor p62 TCF and ElK-1 (2). In conceptors stimulate the serine/threonine kinase activity trast, JNKs phosphorylate the amino terminal transof c-Jun N-terminal kinases (JNKs) was investigated activating domain of c-jun and ATF2 (3), thereby inusing a transient cotransfection experiments in COScreasing their transcriptional activity. 7 cells. Our data demonstrate that JNK activity is po-Although, recent findings have helped to unveil the tently induced by platelet derived growth factor pathway linking cell surface receptors to ERKs, the (PDGF) upon expression of bPDGFR wild type mechanism of activation of JNKs by receptor tyrosine (bRWT). However, PDGF failed to mediate JNK activakinases (RTKs) is less well defined (1,4). Platelet-detion in cells expressing bPDGFR mutant lacking the rived growth factor (PDGF) is a potent mitogen for binding site for phosphatidylinositol-3 (PI-3) kinase connective tissue cells (5). PDGF mediates its diverse but not for phospholipase Cg (PLCg) or Syp. Consisbiological functions by binding to two related high aftent with this result, a PI-3 kinase inhibitor, wortmanfinity receptors designated as aPDGFR and bPDGFR nin inhibited activation of JNK by PDGF. Further-(6,7). Activation of the PDGFR tyrosine kinase domain more, overexpression of P110 the catalytic domain of leads to physical association and tyrosine phosphory-PI-3 kinase was sufficient for activation of JNKs which could be efficiently inhibited by dominant negative lation of many substrates, including Src family memforms of Ras, Rac but not of RhoA or Cdc42. Taken bers Src, yes and fyn, the 85 kDa subunit of PI-3 kitogether all of these findings suggest that activation nase (p85), Nck, RasGTPase-activating protein (Rasof JNK by PDGF involves receptor association with PI-GAP), phospholipase C-g (PLCg) and Syp (8-13). 3 kinase activity, which in turn acts on a ras-and rac-The specific tyrosine residues interacting with each dependent pathway.