DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation

Takahiro Tomino; Hirotada Tajiri; Takaaki Tatsuguchi; Takahiro Shirai; Kounosuke Oisaki; Shigeki Matsunaga; Fumiyuki Sanematsu; Daiji Sakata; Tomoharu Yoshizumi; Yoshihiko Maehara; Motomu Kanai; Jean-François Cote; Yoshinori Fukui; Takehito Uruno

doi:10.1016/j.bbrc.2018.02.073

DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1^P29S mutation

Biochem Biophys Res Commun. 2018 Feb 26;497(1):298-304. doi: 10.1016/j.bbrc.2018.02.073. Epub 2018 Feb 9.

Affiliations

¹ Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
² Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
³ Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Bunkyo-ku, Tokyo, 113-0033, Japan.
⁴ Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12 Nishi-6, Kita-ku, Sapporo, 060-0812, Japan.
⁵ Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Research Center for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
⁶ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
⁷ Institut de recherches cliniques de Montréal, Université de Montréal, 110 avenue des Pins Ouest, Montreal, QC H2W 1R7, Canada.
⁸ Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan; Research Center for Advanced Immunology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. Electronic address: uruno@bioreg.kyushu-u.ac.jp.

PMID: 29432733
DOI: 10.1016/j.bbrc.2018.02.073

Abstract

Rac1 is a member of the Rho family of small GTPases that regulates cytoskeletal reorganization, membrane polarization, cell migration and proliferation. Recently, a self-activating mutation of Rac1, Rac1^P29S, has been identified as a recurrent somatic mutation frequently found in sun-exposed melanomas, which possesses increased inherent GDP/GTP exchange activity and cell transforming ability. However, the role of cellular Rac1-interacting proteins in the transforming potential of Rac1^P29S remains unclear. We found that the catalytic domain of DOCK1, a Rac-specific guanine nucleotide exchange factor (GEF) implicated in malignancy of a variety of cancers, can greatly accelerate the GDP/GTP exchange of Rac1^P29S. Enforced expression of Rac1^P29S induced matrix invasion and macropinocytosis in wild-type (WT) mouse embryonic fibroblasts (MEFs), but not in DOCK1-deficient MEFs. Consistently, a selective inhibitor of DOCK1 that blocks its GEF function suppressed the invasion and macropinocytosis in WT MEFs expressing Rac1^P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1^P29S mutation and express DOCK1 endogenously. Genetic inactivation and pharmacological inhibition of DOCK1 suppressed their invasion and macropinocytosis. Taken together, these results indicate that DOCK1 is a critical regulator of the malignant phenotypes induced by Rac1^P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1^P29S mutation.

Keywords: Cancer; Cytoskeleton; DOCK1; GEF; Invasion; Rac1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line, Tumor
Gene Expression Regulation, Neoplastic / genetics*
Humans
Mutation / genetics
Neoplasm Invasiveness
Neoplasms, Experimental / genetics*
Neoplasms, Experimental / pathology*
Pinocytosis / genetics*
rac GTP-Binding Proteins / antagonists & inhibitors*
rac1 GTP-Binding Protein / genetics*

Substances

DOCK1 protein, human
RAC1 protein, human
rac GTP-Binding Proteins
rac1 GTP-Binding Protein