title: Regulation of immature dendritic cell migration by RhoA guanine nucleotide exchange factor Arhgef5.
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.
authors.affiliation: Program for Vascular Biology and Therapeutics and Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520,, USA.
authors.forename: Zhenglong
authors.initials: Z
authors.lastname: Wang
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kumamoto
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Gan
authors.forename: David
authors.initials: D
authors.lastname: Lehmann
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
authors.forename: Lauren
authors.initials: L
authors.lastname: Cohn
authors.forename: Akiko
authors.initials: A
authors.lastname: Iwasaki
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.forename: Dianqing
authors.initials: D
authors.lastname: Wu
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods; D002465:Cell Movement; D002633:Chemotaxis; D003713:Dendritic Cells / Q000166:cytology*; D005786:Gene Expression Regulation; D020662:Guanine Nucleotide Exchange Factors / Q000096:biosynthesis* / Q000502:physiology; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000502:physiology; D064067:Rho Guanine Nucleotide Exchange Factors; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C577228:ARHGEF5 protein, human; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D010047:Ovalbumin; D008156:Luciferases; D020742:rhoA GTP-Binding Protein