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

Cell migration is a fundamental biological process involving membrane polar ization and cytoskeletal dynamics(1), both of which are regulated by Rho fa mily GTPases(2-5). Among these molecules, Rac is crucial for generating the actin-rich lamellipodial protrusion, a principal part of the driving force for movement(3,6). The CDM family proteins, Caenorhabditis elegans CED-5, human DOCK180 and Drosophila melanogaster Myoblast City (MBC), are implicat ed to mediate membrane extension by functioning upstream of Rac(7-12). Alth ough genetic analysis has shown that CED-5 and Myoblast City are crucial fo r migration of particular types of cells(8,9,12), physiological relevance o f the CDM family proteins in mammals remains unknown. Here we show that DOC K2, a haematopoietic cell-specific CDM family protein(13), is indispensable for lymphocyte chemotaxis. DOCK2-dercient mice (DOCK2(-/-)) exhibited migr ation 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 functio ns as a central regulator that mediates cytoskeletal reorganization through Rac activation.