Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration

• Published in: Nature (London) Vol. 412; no. 6849; pp. 826 - 831
• Main Authors: Fukui, Yoshinori, Hashimoto, Osamu, Sanui, Terukazu, Oono, Takamasa, Koga, Hironori, Abe, Masaaki, Inayoshi, Ayumi, Noda, Mayuko, Oike, Masahiro, Shirai, Toshikazu, Sasazuki, Takehiko
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.08.2001
• Subjects: Animals; B-Lymphocytes - physiology; Caenorhabditis elegans; Carrier Proteins - physiology; Cell Line; Cells; Cellular biology; Chemokine CXCL12; Chemokines, CXC - physiology; Chemotaxis, Leukocyte; Cytokines - physiology; Cytoskeleton - physiology; DOCK2 protein; Drosophila melanogaster; Female; Guanine Nucleotide Exchange Factors; Hematopoietic Stem Cells - physiology; Immunologic Memory; Male; Membranes; Mice; Mice, Inbred C57BL; Proteins; rac GTP-Binding Proteins - physiology; Rac protein; rac1 GTP-Binding Protein; Spleen - cytology; Stem Cells; T-Lymphocytes - physiology
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35090591

Cell migration is a fundamental biological process involving membrane polarization and cytoskeletal dynamics, both of which are regulated by Rho family GTPases. Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement. 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 Rac. Although genetic analysis has shown that CED-5 and Myoblast City are crucial for migration of particular types of cells, physiological relevance of the CDM family proteins in mammals remains unknown. Here we show that DOCK2, a haematopoietic cell-specific CDM family protein, 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.