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Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinase

Oncogene volume 18, pages 1975–1982 (1999)Cite this article

Abstract

Glial cell line-derived neurotrophic factor (GDNF) signals through a unique receptor system that includes Ret receptor tyrosine kinase and a glycosyl-phosphatidylinositol-linked cell surface protein. In the present study, we have identified several proteins in neuroblastoma cells that are phosphorylated on tyrosine in response to GDNF. The phosphorylated proteins include focal adhesion kinase (FAK), paxillin and Crk-associated substrate, p130Cas, all of which are known to be associated with focal adhesions. Of these, paxillin and p130Cas interacted with Crk proteins in GDNF-treated neuroblastoma cells. GDNF also induced reorganization of the actin cytoskelton. Tyrosine phosphorylation of FAK, paxillin and p130Cas was inhibited by cytochalasin D or two specific inhibitors of phosphatidylinositol-3′ kinase (PI-3′ kinase), wortmannin and LY294002, indicating that their tyrosine phosphorylation depends on the formation of actin stress fiber and activation of PI-3′ kinase. In addition, phosphorylation of FAK but not of paxillin and p130Cas was markedly impaired by the Clostridium botulinum C3 exoenzyme that specifically ADP-ribosylates and inactivates Rho. These results suggested the presence of Rho-dependent and -independent signaling pathways downstream of PI-3′ kinase that mediate tyrosine phosphorylation of FAK, paxillin and p130Cas through Ret kinase.

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Acknowledgements

We are grateful to K Imaizumi and J Aoki for technical assistance. This work was supported in part by grants-in-aid for COE research, scientific research and cancer research from the Ministry of Education, Science, Sports and Culture of Japan and by grants from the Cell Science Research Foundation and the Mitsubishi Foundation.

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  1. Department of Pathology, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466, Japan

    Hideki Murakami, Toshihide Iwashita, Naoya Asai, Yosuke Iwata & Masahide Takahashi

  2. Department of Pharmacology, Kyoto University Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto, 606, Japan

    Shuh Narumiya

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Murakami, H., Iwashita, T., Asai, N. et al. Rho-dependent and -independent tyrosine phosphorylation of focal adhesion kinase, paxillin and p130Cas mediated by Ret kinase. Oncogene 18, 1975–1982 (1999). https://doi.org/10.1038/sj.onc.1202514

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