Activation of Rac1 by Rho-guanine nucleotide dissociation inhibitor-β with defective isoprenyl-binding pocket

Authors

  • Takahide Ota,

    Corresponding author
    1. Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Daigaku, Uchinada, Ishikawa 920-0293, Japan
      Corresponding author. Tel.: +81 76 286 2211; fax: +81 76 286 0521. takahide@kanazawa-med.ac.jp
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  • Masayo Maeda,

    1. Department of Chemistry, Kanazawa Medical University, Daigaku, Uchinada, Ishikawa 920-0293, Japan
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  • Manabu Murakami,

    1. Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Daigaku, Uchinada, Ishikawa 920-0293, Japan
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  • Tsutomu Takegami,

    1. Division of Molecular Oncology and Virology, Medical Research Institute, Kanazawa Medical University, Daigaku, Uchinada, Ishikawa 920-0293, Japan
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  • Shiho Suto,

    1. Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
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  • Masaaki Tatsuka

    1. Department of Molecular Radiobiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan
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Corresponding author. Tel.: +81 76 286 2211; fax: +81 76 286 0521. takahide@kanazawa-med.ac.jp

Abstract

Rho-guanine nucleotide dissociation inhibitor-β (RhoGDIβ), a regulator for Rho GTPases, is implicated in cancer cell progression. We reported that C-terminal truncated RhoGDIβ (ΔC(166–201)-RhoGDIβ) promoted metastasis through activating Rac1 signaling pathway in ras-transformed fibroblast cells. To better understand the mechanism of Rac1 activation by ΔC(166–201)-RhoGDIβ during metastasis, the amount of GTP-bound Rac1 was measured as the activation level of Rac1 in cells expressing various mutant RhoGDIβ with sequential C-terminal deletions. Three C-terminal hydrophobic amino acid residues (Trp191, Leu193, and Ile195) supposed to interact with isoprenyl groups of Rac1, was indispensable for a proper regulation of Rac1 activation/inhibition. Deletion of this region led RhoGDIβ to continuously associate with GTP-bound Rac1, provoking constitutive activation of Rac1. Thus, impaired interaction of RhoGDIβ with Rac1 isoprenyl groups possibly makes RhoGDIβ function as a positive regulator for Rac1 during metastasis.

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