Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7.
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 beta-arrestins, which act as versatile adapters controlling receptor signaling, desensitization, and trafficking. Most endogenous receptors appear to signal in a balanced fashion using both beta-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 beta-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 beta-arrestin depletion by siRNA. This example of an endogenous "beta-arrestin-biased" 7TMR that signals through beta-arrestin in the absence of G protein activation demonstrates that some 7TMRs encoded in the genome have evolved to signal through beta-arrestin exclusively and suggests that other receptors that are currently thought to be orphans or decoys may also signal through such nonclassical pathways.
Rajagopal
Sudarshan
S
Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Kim
Jihee
J
Ahn
Seungkirl
S
Craig
Stewart
S
Lam
Christopher M
CM
Gerard
Norma P
NP
Gerard
Craig
C
Lefkowitz
Robert J
RJ
D000818:Animals; D019390:Arrestins / Q000502:physiology*; D002460:Cell Line; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000502:physiology; D006801:Humans; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000502:physiology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D054387:Receptors, CXCR / Q000235:genetics / Q000502:physiology*; D019707:Receptors, Chemokine / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000166:cytology / Q000502:physiology*; D000071557:beta-Arrestins
C501896:ACKR3 protein, human; C501898:Ackr3 protein, rat; D019390:Arrestins; C501897:Cmkor1 protein, mouse; D012333:RNA, Messenger; D054387:Receptors, CXCR; D019707:Receptors, Chemokine; D000071557:beta-Arrestins; D048049:Extracellular Signal-Regulated MAP Kinases; D019204:GTP-Binding Proteins