Differential regulation of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7) by signaling from G protein βγ subunit in human embryonal kidney 293 cells

Heterotrimeric G protein beta gamma subunit (G beta 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 G beta 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. G beta gamma-induced JNK activation was blocked by kinase-deficient MKK4 and to a lesser extent by kinase-deficient MKK7. Moreover, G beta gamma increased MKK4 activity by Q-fold and MKK7 activity by 2-fold. MKK4 activation by G beta gamma was blocked by dominant-negative Rho and Cdc42, whereas MKK7 activation was blocked by dominant-negative Rac. In addition, GP gamma-mediated MKK4 activation, but not MKK7 activation, was inhibited completely by specific tyrosine kinase inhibitors PP2 and PP1. These results indicate that G beta 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.