ROCK and mDia1 antagonize in Rho-dependent Rac activation in Swiss 3T3 fibroblasts

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  • Takahiro Tsuji
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan
  • Toshimasa Ishizaki
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan
  • Muneo Okamoto
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan
  • Chiharu Higashida
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan
  • Kazuhiro Kimura
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan
  • Tomoyuki Furuyashiki
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan
  • Yoshiki Arakawa
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan
  • Raymond B. Birge
    2Department of Biochemistry and Molecular Biology, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, NJ 07214
  • Tetsuya Nakamoto
    3Department of Hematology and Oncology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
  • Hisamaru Hirai
    3Department of Hematology and Oncology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan
  • Shuh Narumiya
    1Department of Pharmacology, Kyoto University Faculty of Medicine, Kyoto 606-8501, Japan

抄録

<jats:p>The small GTPase Rho acts on two effectors, ROCK and mDia1, and induces stress fibers and focal adhesions. However, how ROCK and mDia1 individually regulate signals and dynamics of these structures remains unknown. We stimulated serum-starved Swiss 3T3 fibroblasts with LPA and compared the effects of C3 exoenzyme, a Rho inhibitor, with those of Y-27632, a ROCK inhibitor. Y-27632 treatment suppressed LPA-induced formation of stress fibers and focal adhesions as did C3 exoenzyme but induced membrane ruffles and focal complexes, which were absent in the C3 exoenzyme-treated cells. This phenotype was suppressed by expression of N17Rac. Consistently, the amount of GTP-Rac increased significantly by Y-27632 in LPA-stimulated cells. Biochemically, Y-27632 suppressed tyrosine phosphorylation of paxillin and focal adhesion kinase and not that of Cas. Inhibition of Cas phosphorylation with PP1 or expression of a dominant negative Cas mutant inhibited Y-27632–induced membrane ruffle formation. Moreover, Crk-II mutants lacking in binding to either phosphorylated Cas or DOCK180 suppressed the Y-27632–induced membrane ruffle formation. Finally, expression of a dominant negative mDia1 mutant also inhibited the membrane ruffle formation by Y-27632. Thus, these results have revealed the Rho-dependent Rac activation signaling that is mediated by mDia1 through Cas phosphorylation and antagonized by the action of ROCK.</jats:p>

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