Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration (original) (raw)

Nature volume 412, pages 826–831 (2001)Cite this article

Abstract

Cell migration is a fundamental biological process involving membrane polarization and cytoskeletal dynamics1, both of which are regulated by Rho family GTPases2,3,4,5. Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement3,6. The CDM family proteins, Caenorhabditis elegans CED-5, human DOCK180 and Drosophila melanogaster Myoblast City (MBC), are implicated to mediate membrane extension by functioning upstream of Rac7,8,9,10,11,12. Although genetic analysis has shown that CED-5 and Myoblast City are crucial for migration of particular types of cells8,9,12, physiological relevance of the CDM family proteins in mammals remains unknown. Here we show that DOCK2, a haematopoietic cell-specific CDM family protein13, is indispensable for lymphocyte chemotaxis. DOCK2-deficient mice (DOCK2-/-) exhibited migration defects of T and B lymphocytes, but not of monocytes, in response to chemokines, resulting in several abnormalities including T lymphocytopenia, atrophy of lymphoid follicles and loss of marginal-zone B cells. In DOCK2-/- lymphocytes, chemokine-induced Rac activation and actin polymerization were almost totally abolished. Thus, in lymphocyte migration DOCK2 functions as a central regulator that mediates cytoskeletal reorganization through Rac activation.

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Acknowledgements

We thank K. Matsushima and N. Onai for anti-CXCR4 and anti-CCR7 antibodies; K.-i. Nakayama and K. Nakayama for E14 ES cells and helpful suggestions on ES cell culture; P. Marrack for BEα16-3; and Y. Yamada for blastocyst injection. This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, and CREST, Japan Science and Technology Corporation, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan
    Yoshinori Fukui, Osamu Hashimoto, Terukazu Sanui, Takamasa Oono, Ayumi Inayoshi, Mayuko Noda & Takehiko Sasazuki
  2. Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Asahimachi 67, Kurume, 830-0011, Japan
    Osamu Hashimoto & Hironori Koga
  3. The Second Department of Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, 113-0033, Tokyo, Japan
    Masaaki Abe & Toshikazu Shirai
  4. Department of Pharmacology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan
    Masahiro Oike
  5. International Medical Center of Japan, 1-12-1 Toyama, Shinjuku-ku, 162-8655, Tokyo, Japan
    Takehiko Sasazuki

Authors

  1. Yoshinori Fukui
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  2. Osamu Hashimoto
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  3. Terukazu Sanui
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  4. Takamasa Oono
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  5. Hironori Koga
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  6. Masaaki Abe
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  7. Ayumi Inayoshi
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  8. Mayuko Noda
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  9. Masahiro Oike
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  10. Toshikazu Shirai
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  11. Takehiko Sasazuki
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Correspondence toToshikazu Shirai.

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Fukui, Y., Hashimoto, O., Sanui, T. et al. Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration.Nature 412, 826–831 (2001). https://doi.org/10.1038/35090591

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