RT Journal Article
SR Electronic
T1 β-Arrestin 2-Dependent Angiotensin II Type 1A Receptor-Mediated Pathway of Chemotaxis
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1229
OP 1236
DO 10.1124/mol.104.006270
VO 67
IS 4
A1 Dacia L. Hunton
A1 William G. Barnes
A1 Jihee Kim
A1 Xiu-Rong Ren
A1 Jonathan D. Violin
A1 Eric Reiter
A1 Graeme Milligan
A1 Dhavalkumar D. Patel
A1 Robert J. Lefkowitz
YR 2005
UL http://molpharm.aspetjournals.org/content/67/4/1229.abstract
AB 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 Gαi family. β-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 β-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 Gαi. Suppression of β-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 Gαq/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 β-arrestin 2 can mediate chemotaxis through mechanisms which may be G-protein-independent (Ang II receptors) or -dependent (LPA receptors).