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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Robert J. Lefkowitz
The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win. Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the
Dhavalkumar Dhirajlal Patel
Associate Consulting Professor in the Department of Medicine
The overall goals of the Patel laboratory are two-fold: 1) to define the mechanisms of inflammation, focusing on signaling through G protein coupled receptors, for the purpose of identifying novel therapeutic targets for immunologic diseases; and 2) to define the role that T cell education in the thymus plays in diseases of disordered immunity such as autoimmune diseases and primary immunodeficiency syndromes. 1. Roles of Membrane-Tethered Chemokines in Inflammation. Based on o
Richard Thomas Premont
Associate Professor in Medicine
Critical physiological events throughout the body are controlled by extracellular signals from neurotransmitters and hormones acting on cell surface receptors. Receptors transduce these signals to alter intracellular metabolism and cellular responsiveness through heterotrimeric G protein/second messenger pathways or through small GTP-binding protein/protein kinase cascades. The mechanisms that control the responsiveness of target organ G protein-coupled receptors include receptor ph
Yen-Rei Andrea Yu
Adjunct Assistant Professor in the Department of Medicine
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