Haematopoietic cell-specific CDM family protein DOCK2 is essential for lymphocyte migration.
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.
Fukui
Y
Y
Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, and CREST, Japan.
Hashimoto
O
O
Sanui
T
T
Oono
T
T
Koga
H
H
Abe
M
M
Inayoshi
A
A
Noda
M
M
Oike
M
M
Shirai
T
T
Sasazuki
T
T
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D005260:Female; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D007156:Immunologic Memory; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000166:cytology; D013234:Stem Cells; D013601:T-Lymphocytes / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000502:physiology; D020830:rac1 GTP-Binding Protein
C515255:CXCL12 protein, human; D002352:Carrier Proteins; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D016207:Cytokines; C402110:DOCK2 protein, human; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein