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-Arrestin 2-Dependent Angiotensin II Type 1A Receptor-Mediated Pathway of Chemotaxis
Howard Hughes Medical Institute (D.L.H., R.J.L.) and Departments of Biochemistry and Medicine (W.G.B., J.K., X-R.R., J.V., E.R., R.J.L.), Duke University Medical Center, Durham, North Carolina; Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, Scotland (G.M.); and Departments of Medicine and Microbiology and Immunology, Division of Rheumatology, Allergy and Immunology, Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, North Carolina (D.D.P.)
Abstract
Chemotaxis is a cellular response that directs cell migration toward a chemical gradient and is fundamental to a variety of cellular processes. The receptors for most known chemokines belong to the seven transmembrane-spanning superfamily and signal through members of the G
i family. 
-Arrestins, in addition to regulating desensitization, have emerged as potential mediators of G-protein-independent signaling pathways and have been implicated in several chemotactic pathways. Here, we report a system wherein chemotaxis is stimulated in a -arrestin 2-dependent and apparently G-protein-independent manner. Human embryonic kidney 293 cells with stable expression of the angiotensin II (Ang II) receptor type 1A (AT1AR) undergo chemotaxis in response to Ang II. An Ang II peptide analog S1I4I8 Ang II that is unable to activate G-protein-mediated responses induces chemotaxis in these cells that is unaffected by pertussis toxin-mediated suppression of Gi. Suppression of -arrestin 2 expression using small interfering RNA (siRNA) essentially eliminated AT1AR-mediated chemotaxis induced by either Ang II or the S1I4I8 Ang II peptide but had no effect on epidermal growth factor (EGF)-induced chemotaxis. It also abolished chemotaxis induced by lysophosphatidic acid (LPA), which was completely sensitive to pertussis toxin. In contrast, reduction of Gq/11 through siRNA and inhibition of protein kinase C, extracellular signal-regulated kinases 1 and 2, or phosphatidylinositol-3-kinase did not diminish AT1AR-mediated chemotaxis. Inhibiting p38 mitogen-activated protein kinase decreased AT1AR-mediated chemotaxis and eliminated EGF-mediated chemotaxis, suggesting that p38 plays a role in chemotaxis that is not specific to the AT1AR in this system. These data suggest that -arrestin 2 can mediate chemotaxis through mechanisms which may be G-protein-independent (Ang II receptors) or -dependent (LPA receptors).
Address correspondence to: Dr. Robert J. Lefkowitz, Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Box 3821, Duke University Medical Center, Durham, NC 27710. E-mail: lefko001{at}receptor-biol.duke.edu
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