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J. Biol. Chem. 286 (37): 32188-32197

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

CXCR7/CXCR4 Heterodimer Constitutively Recruits β-Arrestin to Enhance Cell Migration*Formula

Fabien M. Décaillot1, Manija A. Kazmi, Ying Lin, Sarmistha Ray-Saha, Thomas P. Sakmar2, , and Pallavi Sachdev3

From the Laboratory of Molecular Biology and Biochemistry, Rockefeller University, New York, New York 10065

ABSTRACT Back to Top

Abstract: G protein-coupled receptor hetero-oligomerization is emerging as an important regulator of ligand-dependent transmembrane signaling, but precisely how receptor heteromers affect receptor pharmacology remains largely unknown. In this study, we have attempted to identify the functional significance of the heteromeric complex between CXCR4 and CXCR7 chemokine receptors. We demonstrate that co-expression of CXCR7 with CXCR4 results in constitutive recruitment of β-arrestin to the CXCR4·CXCR7 complex and simultaneous impairment of Gi-mediated signaling. CXCR7/CXCR4 co-expression also results in potentiation of CXCL12 (SDF-1)-mediated downstream β-arrestin-dependent cell signaling pathways, including ERK1/2, p38 MAPK, and SAPK as judged from the results of experiments using siRNA knockdown to deplete β-arrestin. Interestingly, CXCR7/CXCR4 co-expression enhances cell migration in response to CXCL12 stimulation. Again, inhibition of β-arrestin using either siRNA knockdown or a dominant negative mutant abrogates the enhanced CXCL12-dependent migration of CXCR4/CXCR7-expressing cells. These results show how CXCR7, which cannot signal directly through G protein-linked pathways, can nevertheless affect cellular signaling networks by forming a heteromeric complex with CXCR4. The CXCR4·CXCR7 heterodimer complex recruits β-arrestin, resulting in preferential activation of β-arrestin-linked signaling pathways over canonical G protein pathways. CXCL12-dependent signaling of CXCR4 and its role in cellular physiology, including cancer metastasis, should be evaluated in the context of potential functional hetero-oligomerization with CXCR7.

Key Words: 7-Helix Receptor • Cell Migration • Chemokines • Heterotrimeric G Proteins • MAPKs

Received for publication June 29, 2011.

FOOTNOTES Back to Top

1 Present address: Singapore Immunology Network (SigN), 8A Biomedical Grove, Immunos Bldg. 3–4, Biopolis, 138648, Singapore.

2 To whom correspondence may be addressed: Laboratory of Molecular Biology and Biochemistry, Rockefeller University, 1230 York Ave., New York, NY 10065. Tel.: 212-327-8284; Fax: 212-327-7904; E-mail: sakmar{at}rockefeller.edu.

3 To whom correspondence may be addressed: Eisai, Inc., 300 Tice Blvd., Woodcliff Lake, NJ 07677. E-mail: Pallavi_Sachdev{at}eisai.com.

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
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