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PNAS 107 (2): 628-632

Copyright © 2010 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / BIOCHEMISTRY

β-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7

Sudarshan Rajagopala, Jihee Kima, Seungkirl Ahna, Stewart Craigb,c, Christopher M. Lama, Norma P. Gerardb,c, Craig Gerardb,c,1, and Robert J. Lefkowitza,d,e,1

aDepartment of Medicine, Duke University Medical Center, Durham, NC 27710; bPulmonary Division, Department of Pediatrics, Children’s Hospital, Boston, MA 02115; cDepartment of Medicine, Harvard Medical School, Boston, MA 02115; dDepartment of Biochemistry, Duke University Medical Center, Durham, NC 27710; and eHoward Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710

Contributed by Robert J. Lefkowitz, November 9, 2009 (sent for review October 1, 2009)

Abstract: Ubiquitously expressed seven-transmembrane receptors (7TMRs) classically signal through heterotrimeric G proteins and are commonly referred to as G protein-coupled receptors. It is now recognized that 7TMRs also signal through β-arrestins, which act as versatile adapters controlling receptor signaling, desensitization, and trafficking. Most endogenous receptors appear to signal in a balanced fashion using both β-arrestin and G protein-mediated pathways. Some 7TMRs are thought to be nonsignaling "decoys" because of their inability to activate typical G protein signaling pathways; it has been proposed that these receptors act to scavenge ligands or function as coreceptors. Here we demonstrate that ligand binding to the decoy receptor CXCR7 does not result in activation of signaling pathways typical of G proteins but does activate MAP kinases through β-arrestins in transiently transfected cells. Furthermore, we observe that vascular smooth muscle cells that endogenously express CXCR7 migrate to its ligand interferon-inducible T-cell alpha chemoattractant (ITAC), an effect that is significantly attenuated by treatment with either a CXCR7 antagonist or β-arrestin depletion by siRNA. This example of an endogenous "β-arrestin-biased" 7TMR that signals through β-arrestin in the absence of G protein activation demonstrates that some 7TMRs encoded in the genome have evolved to signal through β-arrestin exclusively and suggests that other receptors that are currently thought to be orphans or decoys may also signal through such nonclassical pathways.

Key Words: biased receptor • chemokine • G protein-coupled receptors • seven-transmembrane receptor

Author contributions: S.R., J.K., S.A., N.P.G., C.G., and R.J.L. designed research; S.R., J.K., S.C., C.M.L., and N.P.G. performed research; S.R., J.K., S.C., and N.P.G. analyzed data; S.R., C.G., and R.J.L. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0912852107/DCSupplemental.

1To whom correspondence may be addressed. E-mail: Craig.Gerard{at}childrens.harvard.edu or lefko001{at}receptor-biol.duke.edu.

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