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Beta-arrestin- but not G protein-mediated signaling by the "decoy" receptor CXCR7
Sudarshan Rajagopal1, Jihee Kim, Seungkirl Ahn
1Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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 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.
Insights
Seven-transmembrane receptors (7TMRs) can signal through beta-arrestins, not just G proteins. The decoy receptor CXCR7 exclusively uses beta-arrestin signaling for cell migration, challenging traditional receptor function models.
Area of Science:
- Cellular signaling pathways
- Molecular and cellular biology
- Receptor pharmacology
Background:
- Seven-transmembrane receptors (7TMRs), also known as G protein-coupled receptors, classically signal via G proteins.
- Emerging evidence shows 7TMRs also signal through beta-arrestins, which regulate receptor desensitization and trafficking.
- Some 7TMRs are considered 'decoys' due to a lack of G protein activation, potentially scavenging ligands or acting as coreceptors.
Purpose of the Study:
- To investigate the signaling mechanisms of the decoy receptor CXCR7.
- To determine if CXCR7 utilizes beta-arrestin pathways for signaling.
- To explore the role of CXCR7 and beta-arrestin signaling in cellular functions like migration.
Main Methods:
- Ligand binding assays and MAP kinase activation studies in transiently transfected cells.
- Assessment of vascular smooth muscle cell migration in response to the CXCR7 ligand ITAC.
- Utilizing a CXCR7 antagonist and siRNA-mediated beta-arrestin depletion to dissect signaling pathways.
Main Results:
- CXCR7 ligand binding did not activate G protein pathways but induced MAP kinase activation via beta-arrestins in transfected cells.
- Endogenous CXCR7 in vascular smooth muscle cells mediated cell migration towards ITAC.
- CXCR7-mediated migration was significantly reduced by CXCR7 antagonism and beta-arrestin depletion.
Conclusions:
- CXCR7 functions as a "beta-arrestin-biased" receptor, exclusively signaling through beta-arrestins without G protein activation.
- This study provides evidence that some 7TMRs have evolved for exclusive beta-arrestin signaling.
- Orphan or decoy receptors may utilize nonclassical signaling pathways, expanding the known repertoire of 7TMR functions.
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