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

研究成果: ジャーナルへの寄稿記事

5 引用 (Scopus)

抄録

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, Rac1P29S, 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 Rac1P29S 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 Rac1P29S. Enforced expression of Rac1P29S 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 Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S 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 Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation.

元の言語英語
ページ(範囲)298-304
ページ数7
ジャーナルBiochemical and Biophysical Research Communications
497
発行部数1
DOI
出版物ステータス出版済み - 2 26 2018

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Fibroblasts
Guanine Nucleotide Exchange Factors
Cells
Guanosine Triphosphate
Mutation
Melanoma
Neoplasms
rac1 GTP-Binding Protein
Monomeric GTP-Binding Proteins
Ports and harbors
Sun
Aptitude
Solar System
Polarization
Cell Movement
Membranes
Catalytic Domain
Cell Proliferation
Pharmacology
Breast Neoplasms

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

これを引用

DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation. / Tomino, Takahiro; Tajiri, Hirotada; Tatsuguchi, Takaaki; Shirai, Takahiro; Oisaki, Kounosuke; Matsunaga, Shigeki; Sanematsu, Fumiyuki; Sakata, Daiji; Yoshizumi, Tomoharu; Maehara, Yoshihiko; Kanai, Motomu; Cote, Jean François; Fukui, Yoshinori; Uruno, Takehito.

:: Biochemical and Biophysical Research Communications, 巻 497, 番号 1, 26.02.2018, p. 298-304.

研究成果: ジャーナルへの寄稿記事

Tomino, Takahiro ; Tajiri, Hirotada ; Tatsuguchi, Takaaki ; Shirai, Takahiro ; Oisaki, Kounosuke ; Matsunaga, Shigeki ; Sanematsu, Fumiyuki ; Sakata, Daiji ; Yoshizumi, Tomoharu ; Maehara, Yoshihiko ; Kanai, Motomu ; Cote, Jean François ; Fukui, Yoshinori ; Uruno, Takehito. / DOCK1 inhibition suppresses cancer cell invasion and macropinocytosis induced by self-activating Rac1P29S mutation. :: Biochemical and Biophysical Research Communications. 2018 ; 巻 497, 番号 1. pp. 298-304.
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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, Rac1P29S, 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 Rac1P29S 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 Rac1P29S. Enforced expression of Rac1P29S 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 Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S 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 Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation.",
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AU - Tomino, Takahiro

AU - Tajiri, Hirotada

AU - Tatsuguchi, Takaaki

AU - Shirai, Takahiro

AU - Oisaki, Kounosuke

AU - Matsunaga, Shigeki

AU - Sanematsu, Fumiyuki

AU - Sakata, Daiji

AU - Yoshizumi, Tomoharu

AU - Maehara, Yoshihiko

AU - Kanai, Motomu

AU - Cote, Jean François

AU - Fukui, Yoshinori

AU - Uruno, Takehito

PY - 2018/2/26

Y1 - 2018/2/26

N2 - 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, Rac1P29S, 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 Rac1P29S 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 Rac1P29S. Enforced expression of Rac1P29S 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 Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S 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 Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation.

AB - 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, Rac1P29S, 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 Rac1P29S 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 Rac1P29S. Enforced expression of Rac1P29S 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 Rac1P29S. Human melanoma IGR-1 and breast cancer MDA-MB-157 cells harbor Rac1P29S 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 Rac1P29S, and suggest that targeting DOCK1 might be an effective approach to treat cancers associated with Rac1P29S mutation.

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