Involvement of protein kinase C and Src family tyrosine kinase in Gαq/11-induced activation of c-jun N-terminal kinase and p38 mitogen-activated protein kinase

Mitogen-activated protein kinases (MAPKs) are activated by various extracellular stimuli. The signaling pathways from G protein-coupled receptors to extracellular signal-regulated kinase have been partially elucidated, whereas the mechanisms by which G protein-coupled receptors stimulate c-Jun N-terminal kinase (JNK) and p38 MAPK activities remain largely unknown. We have recently demonstrated that the signal from G(q/11)-coupled mi muscarinic acetylcholine receptor to p38 MAPK is mediated by both G alpha(q/11) and G beta gamma in HEK-293 cells (Yamauchi, J., Nagao, M., Kaziro, Y., and Itoh, H. (1997) J. Biol. Chem. 272, 27771-27777). In the present study, we report that a constitutively activated mutant of G alpha(11) (G alpha(11) Q209L) activated not only p38 MAPK but also JNK, and the activation of JNK and p38 MAPK by Ga-11 Q209L was partially inhibited by prolonged treatment with phorbol 12-myristate 13-acetate and calphostin C. In addition, the G alpha(11) Q209L-stimulated activation of both kinases was blocked by a specific inhibitor of protein tyrosine kinases (PP2) and Csk ((C) under bar-terminal (S) under bar rc (k) under bar inase). Furthermore, we demonstrated that Gall Q209L stimulated Src family kinase activity and induced tyrosine phosphorylation of several proteins in HEK-293 cells. These results suggest that G alpha(q/11) stimulates JNK and p38 MAPK activities through protein kinase C- and Src family kinase-dependent signaling pathways.