Requirement of Phosphatidylinositol-3 Kinase for Activation of JNK/SAPKs by PDGF

• Published in: Biochemical and biophysical research communications Vol. 232; no. 2; pp. 273 - 277
• Main Authors: Lopez-Ilasaca, Marco, Li, Weiqun, Uren, Aykut, Yu, Jin-chen, Kazlauskas, Andrius, Gutkind, J.Silvio, Heidaran, Mohammad A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.1997
• Subjects: Androstadienes - pharmacology; Animals; Calcium-Calmodulin-Dependent Protein Kinases - antagonists & inhibitors; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; COS Cells; Enzyme Activation - drug effects; GTP-Binding Proteins - physiology; JNK Mitogen-Activated Protein Kinases; Ligands; Mitogen-Activated Protein Kinases; Phosphatidylinositol 3-Kinases; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor) - antagonists & inhibitors; Phosphotransferases (Alcohol Group Acceptor) - physiology; Platelet-Derived Growth Factor - metabolism; Platelet-Derived Growth Factor - pharmacology; Proto-Oncogene Proteins p21(ras) - pharmacology; Receptor, Platelet-Derived Growth Factor beta; Receptors, Platelet-Derived Growth Factor - metabolism; Receptors, Platelet-Derived Growth Factor - physiology; rho GTP-Binding Proteins; Tyrosine - metabolism
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.1997.6289

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 βPDGFR wild type (βRWT). However, PDGF failed to mediate JNK activation in cells expressing βPDGFR mutant lacking the binding site for phosphatidylinositol-3 (PI-3) kinase but not for phospholipase Cγ (PLCγ) 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.