Differential regulation of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7) by signaling from G protein beta gamma subunit in human embryonal kidney 293 cells.
Heterotrimeric G protein beta gamma subunit (Gbeta gamma) mediates signals to two types of stress-activated protein kinases, c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase, in mammalian cells. To investigate the signaling mechanism whereby Gbeta gamma regulates the activity of JNK, we transfected kinase-deficient mutants of two JNK kinases, mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7), into human embryonal kidney 293 cells. Gbeta gamma-induced JNK activation was blocked by kinase-deficient MKK4 and to a lesser extent by kinase-deficient MKK7. Moreover, Gbeta gamma increased MKK4 activity by 6-fold and MKK7 activity by 2-fold. MKK4 activation by Gbeta gamma was blocked by dominant-negative Rho and Cdc42, whereas MKK7 activation was blocked by dominant-negative Rac. In addition, Gbeta gamma-mediated MKK4 activation, but not MKK7 activation, was inhibited completely by specific tyrosine kinase inhibitors PP2 and PP1. These results indicate that Gbeta gamma induces JNK activation mainly through MKK4 activation dependent on Rho, Cdc42, and tyrosine kinase, and to a lesser extent through MKK7 activation dependent on Rac.
Yamauchi
J
J
Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan.
Kaziro
Y
Y
Itoh
H
H
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002460:Cell Line; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D011976:Receptors, Muscarinic; D011494:Protein Kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D048688:MAP Kinase Kinase 7; C482559:MAP2K4 protein, human; C482569:MAP2K7 protein, human; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D018631:ras Proteins