MECHANISMS OF SIGNAL TRANSDUCTION
Gi-dependent Activation of c-Jun N-terminal Kinase in Human Embryonal Kidney 293 Cells*

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Heterotrimeric G proteins stimulate the activities of two stress-activated protein kinases, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase in mammalian cells. In this study, we examined whether α subunits of Gi family activate JNK using transient expression system in human embryonal kidney 293 cells. Constitutively activated mutants of Gαi1, Gαi2, and Gαi3 increased JNK activity. In contrast, constitutively activated Gαo and Gαz mutants did not stimulate JNK activity. To examine the mechanism of JNK activation by Gαi, kinase-deficient mutants of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7), which are known to be JNK activators, were transfected into the cells. However, Gαi-induced JNK activation was not blocked effectively by kinase-deficient MKK4 and MKK7. In addition, activated Gαi mutant failed to stimulate MKK4 and MKK7 activities. Furthermore, JNK activation by Gαi was inhibited by dominant-negative Rho and Cdc42 and tyrosine kinase inhibitors, but not dominant-negative Rac and phosphatidylinositol 3-kinase inhibitors. These results indicate that Gαi regulates JNK activity dependent on small GTPases Rho and Cdc42 and on tyrosine kinase but not on MKK4 and MKK7.

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This work was supported by grants from CREST and from the Ministry of Education, Science, Sports, and Culture. Our laboratory is funded by Schering-Plough Corporation.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.