Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice.
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Lymphocyte chemotaxis is a complex process by which cells move within tissues and across barriers such as vascular endothelium and is usually stimulated by chemokines such as stromal cell-derived factor-1 (CXCL12) acting via G protein-coupled receptors. Because members of this receptor family are regulated ("desensitized") by G protein-coupled receptor kinase (GRK)-mediated receptor phosphorylation and beta-arrestin binding, we examined signaling and chemotactic responses in splenocytes derived from knockout mice deficient in various beta-arrestins and GRKs, with the expectation that these responses might be enhanced. Knockouts of beta-arrestin2, GRK5, and GRK6 were examined because all three proteins are expressed at high levels in purified mouse CD3+ T and B220+ B splenocytes. CXCL12 stimulation of membrane GTPase activity was unaffected in splenocytes derived from GRK5-deficient mice but was increased in splenocytes from the beta-arrestin2- and GRK6-deficient animals. Surprisingly, however, both T and B cells from beta-arrestin2-deficient animals and T cells from GRK6-deficient animals were strikingly impaired in their ability to respond to CXCL12 both in transwell migration assays and in transendothelial migration assays. Chemotactic responses of lymphocytes from GRK5-deficient mice were unaffected. Thus, these results indicate that beta-arrestin2 and GRK6 actually play positive regulatory roles in mediating the chemotactic responses of T and B lymphocytes to CXCL12.
G-Protein-Coupled Receptor Kinase 5
G-Protein-Coupled Receptor Kinases
Gene Expression Regulation
Mice, Inbred C57BL
Published Version (Please cite this version)10.1073/pnas.112198299
Publication InfoFong, Alan M; Premont, Richard T; Richardson, Ricardo M; Yu, Yen-Rei A; Lefkowitz, Robert J; & Patel, Dhavalkumar D (2002). Defective lymphocyte chemotaxis in beta-arrestin2- and GRK6-deficient mice. Proc Natl Acad Sci U S A, 99(11). pp. 7478-7483. 10.1073/pnas.112198299. Retrieved from https://hdl.handle.net/10161/7804.
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