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

Nature. 2001 Aug 23;412(6849):826-31. doi: 10.1038/35090591.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / physiology*
  • Carrier Proteins / physiology*
  • Cell Line
  • Chemokine CXCL12
  • Chemokines, CXC / physiology
  • Chemotaxis, Leukocyte*
  • Cytokines / physiology
  • Cytoskeleton / physiology
  • Female
  • Guanine Nucleotide Exchange Factors*
  • Hematopoietic Stem Cells / physiology*
  • Immunologic Memory
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Spleen / cytology
  • Stem Cells
  • T-Lymphocytes / physiology*
  • rac GTP-Binding Proteins / physiology
  • rac1 GTP-Binding Protein*

Substances

  • CXCL12 protein, human
  • Carrier Proteins
  • Chemokine CXCL12
  • Chemokines, CXC
  • Cxcl12 protein, mouse
  • Cytokines
  • DOCK2 protein, human
  • Guanine Nucleotide Exchange Factors
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein