Article

Regulation of immature dendritic cell migration by RhoA guanine nucleotide exchange factor Arhgef5.

Program for Vascular Biology and Therapeutics and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520,, USA.
Journal of Biological Chemistry (impact factor: 4.77). 09/2009; 284(42):28599-606. DOI:10.1074/jbc.M109.047282 pp.28599-606
Source: PubMed

ABSTRACT There are a large number of Rho guanine nucleotide exchange factors, most of which have no known functions. Here, we carried out a short hairpin RNA-based functional screen of Rho-GEFs for their roles in leukocyte chemotaxis and identified Arhgef5 as an important factor in chemotaxis of a macrophage phage-like RAW264.7 cell line. Arhgef5 can strongly activate RhoA and RhoB and weakly RhoC and RhoG, but not Rac1, RhoQ, RhoD, or RhoV, in transfected human embryonic kidney 293 cells. In addition, Gbetagamma interacts with Arhgef5 and can stimulate Arhgef5-mediated activation of RhoA in an in vitro assay. In vivo roles of Arhgef5 were investigated using an Arhgef-5-null mouse line. Arhgef5 deficiency did not affect chemotaxis of mouse macrophages, T and B lymphocytes, and bone marrow-derived mature dendritic cells (DC), but it abrogated MIP1alpha-induced chemotaxis of immature DCs and impaired migration of DCs from the skin to lymph node. In addition, Arhgef5 deficiency attenuated allergic airway inflammation. Therefore, this study provides new insights into signaling mechanisms for DC migration regulation.

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Keywords

Arhgef-5-null mouse line
 
Arhgef5 deficiency
 
Arhgef5 deficiency attenuated allergic airway inflammation
 
B lymphocytes
 
bone marrow-derived mature dendritic cells
 
DC migration regulation
 
Gbetagamma interacts
 
immature DCs
 
known functions
 
lymph node
 
macrophage phage-like RAW264.7 cell line
 
mouse macrophages
 
new insights
 
Rho guanine nucleotide exchange factors
 
RhoB
 
RhoV
 
short hairpin RNA-based functional screen
 
transfected human embryonic kidney 293 cells
 
weakly RhoC
 

Zhenglong Wang