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) was investigated using a transient cotransfection experiments in COS-7 cells. Our data demonstrate that JNK activity is potently induced by platelet derived growth factor (PDGF) upon expression of beta PDGFR wild type (beta RWT). However, PDGF failed to mediate JNK activation in cells expressing beta PDGFR mutant lacking the binding site for phosphatidylinositol-3 (PI-3) kinase but not for phospholipase C gamma (PLC gamma) or Syp. Consistent with this result, a PI-3 kinase inhibitor, wortmannin inhibited activation of JNK by PDGF. Furthermore, overexpression of P110 the catalytic domain of PI-3 kinase was sufficient for activation of JNKs which could be efficiently inhibited by dominant negative forms of Ras, Rac but not of RhoA or Cdc42. Taken together all of these findings suggest that activation of JNK by PDGF involves receptor association with PI-3 kinase activity, which in turn acts on a ras- and rac-dependent pathway.
Lopez-Ilasaca
M
M
Max-Planck Research Group, Faculty of Medicine, Friedrich Schiller Universität, Jena, Germany.
Li
W
W
Uren
A
A
Yu
J C
JC
Kazlauskas
A
A
Gutkind
J S
JS
Heidaran
M A
MA
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000502:physiology; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D000077191:Wortmannin; D020741:rho GTP-Binding Proteins
D000730:Androstadienes; D008024:Ligands; D010982:Platelet-Derived Growth Factor; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D019204:GTP-Binding Proteins; D016283:Proto-Oncogene Proteins p21(ras); D020741:rho GTP-Binding Proteins; D000077191:Wortmannin