Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

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:
CXCR4 drives the metastatic phenotype in breast cancer through induction of CXCR2 and activation of MEK and PI3K pathways.
T. Sobolik, Y.-j. Su, S. Wells, G. D. Ayers, R. S. Cook, and A. Richmond (2014)
Mol. Biol. Cell 25, 566-582
   Abstract »    Full Text »    PDF »
CXCR7 Upregulation Is Required for Early Endothelial Progenitor Cell-Mediated Endothelial Repair in Patients With Hypertension.
X.-Y. Zhang, C. Su, Z. Cao, S.-Y. Xu, W.-H. Xia, W.-L. Xie, L. Chen, B.-B. Yu, B. Zhang, Y. Wang, et al. (2014)
Hypertension 63, 383-389
   Abstract »    Full Text »    PDF »
CXCR7 participates in CXCL12-induced CD34+ cell cycling through {beta}-arrestin-dependent Akt activation.
F. Torossian, A. Anginot, A. Chabanon, D. Clay, B. Guerton, C. Desterke, L. Boutin, S. Marullo, M. G. H. Scott, J.-J. Lataillade, et al. (2014)
Blood 123, 191-202
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors.
F. Bachelerie, A. Ben-Baruch, A. M. Burkhardt, C. Combadiere, J. M. Farber, G. J. Graham, R. Horuk, A. H. Sparre-Ulrich, M. Locati, A. D. Luster, et al. (2014)
Pharmacol. Rev. 66, 1-79
   Abstract »    Full Text »    PDF »
Phosphorylation of chemoattractant receptors regulates chemotaxis, actin reorganization and signal relay.
J. A. Brzostowski, S. Sawai, O. Rozov, X.-h. Liao, D. Imoto, C. A. Parent, and A. R. Kimmel (2013)
J. Cell Sci. 126, 4614-4626
   Abstract »    Full Text »    PDF »
Response to Comment on "CXCL9 Causes Heterologous Desensitization of CXCL12-Mediated Memory T Lymphocyte Activation".
O. Giegold, N. Ogrissek, and H. H. Radeke (2013)
J. Immunol. 191, 525-526
   Full Text »    PDF »
Use of G-Protein-Coupled and -Uncoupled CCR5 Receptors by CCR5 Inhibitor-Resistant and -Sensitive Human Immunodeficiency Virus Type 1 Variants.
R. Berro, A. Yasmeen, R. Abrol, B. Trzaskowski, S. Abi-Habib, A. Grunbeck, D. Lascano, W. A. Goddard III, P. J. Klasse, T. P. Sakmar, et al. (2013)
J. Virol. 87, 6569-6581
   Abstract »    Full Text »    PDF »
Induction of C-X-C Chemokine Receptor Type 7 (CXCR7) Switches Stromal Cell-derived Factor-1 (SDF-1) Signaling and Phagocytic Activity in Macrophages Linked to Atherosclerosis.
W. Ma, Y. Liu, N. Ellison, and J. Shen (2013)
J. Biol. Chem. 288, 15481-15494
   Abstract »    Full Text »    PDF »
International Union of Basic and Clinical Pharmacology. LXXXVII. Complement Peptide C5a, C4a, and C3a Receptors.
A. Klos, E. Wende, K. J. Wareham, and P. N. Monk (2013)
Pharmacol. Rev. 65, 500-543
   Abstract »    Full Text »    PDF »
CXCR4-Based Imaging Agents.
L. E. Woodard and S. Nimmagadda (2011)
J. Nucl. Med. 52, 1665-1669
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882