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The Src family tyrosine kinase is involved in Rho-dependent activation of c-Jun N-terminal kinase by Gα12

Oncogene volume 18, pages 4425–4434 (1999)Cite this article

Abstract

Gα12, a member of α subunit of heterotrimeric G protein G12 subfamily, has been shown to stimulate c-Jun N-terminal kinase (JNK) activity through the low molecular weight GTP-binding proteins Ras, Rac, and Cdc42. In this study using the transient expression of a constitutively activated mutant of Gα12 (Gα12Q229L) in human embryonic kidney (HEK) 293 cells, we found that Rho and Src family kinase are also involved in the Gα12-induced activation of JNK. The activation of JNK by Gα12Q229L was inhibited by dominant-negative RhoA(T19N), and botulinum C3 exoenzyme which specifically inactivates Rho. In addition, the expression of activated RhoA(G14V) elevated JNK activity in HEK 293 cells. The Gα12Q229L-stimulated activation of JNK was blocked by a specific inhibitor of protein tyrosine kinases (PP2), and C-terminal Src kinase (Csk). Moreover, we observed that Gα12Q229L stimulated Src family kinase activity and v-Src induced JNK activation. Interestingly, the v-Src-induced activation of JNK was inhibited by dominant-negative RhoA(T19N). In contrast, Csk did not inhibit the JNK activation by activated RhoA(G14V). These results suggest that Rho and Src family kinase are required for the Gα12-induced JNK activation, and that Src family kinase acts upstream of Rho activation in the JNK pathway.

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Acknowledgements

We thank Dr A Levitzki for the generous gift of PP2/AG1879 and Drs M Karin, K Kaibuchi, M Takada, M Okada, GM Cooper, S Narumiya and Y Fukami for kindly providing us with expression plasmids. We also thank Drs J Yamauchi, H Koide and S Mizutani for helpful discussions and K Tsumaya, J Suzuki, and Y Yamazaki for plasmids construction. This work was supported by a grant from CREST (Core Research for Evolutional Science and Technology) and by research fellowships (to MN) from the Japan Society for the Promotion of Science for Young Scientists. Our laboratory is supported by funding from Schering-Plough Corporation.

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  1. Faculty of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan

    Motoshi Nagao, Yoshito Kaziro & Hiroshi Itoh

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  1. Motoshi Nagao
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  2. Yoshito Kaziro
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Nagao, M., Kaziro, Y. & Itoh, H. The Src family tyrosine kinase is involved in Rho-dependent activation of c-Jun N-terminal kinase by Gα12. Oncogene 18, 4425–4434 (1999). https://doi.org/10.1038/sj.onc.1202832

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