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Published online 28 August 2006 doi:10.1084/jem.20052144
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 9, 2201-2213
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ARTICLE

 A novel chemokine receptor for SDF-1 and I-TAC involved in cell survival, cell adhesion, and tumor development

Jennifer M. Burns1, Bretton C. Summers1, Yu Wang1, Anita Melikian1, Rob Berahovich1, Zhenhua Miao1, Mark E. T. Penfold1, Mary Jean Sunshine2, Dan R. Littman2, Calvin J. Kuo3, Kevin Wei3, Brian E. McMaster1, Kim Wright1, Maureen C. Howard1, and Thomas J. Schall1

1 ChemoCentryx, Inc., Mountain View, CA 94043
2 Skirball Institute of Biomolecular Medicine, New York University Medical Center, New York, NY 10016
3 Division of Hematology, Stanford University School of Medicine, Stanford, CA 94305

CORRESPONDENCE Thomas J. Schall: tschall{at}chemocentryx.com

The chemokine stromal cell–derived factor (SDF-1; also known as chemokine ligand 12 [CXCL12]) regulates many essential biological processes, including cardiac and neuronal development, stem cell motility, neovascularization, angiogenesis, apoptosis, and tumorigenesis. It is generally believed that SDF-1 mediates these many disparate processes via a single cell surface receptor known as chemokine receptor 4 (CXCR4). This paper characterizes an alternate receptor, CXCR7, which binds with high affinity to SDF-1 and to a second chemokine, interferon-inducible T cell {alpha} chemoattractant (I-TAC; also known as CXCL11). Membrane-associated CXCR7 is expressed on many tumor cell lines, on activated endothelial cells, and on fetal liver cells, but on few other cell types. Unlike many other chemokine receptors, ligand activation of CXCR7 does not cause Ca2+ mobilization or cell migration. However, expression of CXCR7 provides cells with a growth and survival advantage and increased adhesion properties. Consistent with a role for CXCR7 in cell survival and adhesion, a specific, high affinity small molecule antagonist to CXCR7 impedes in vivo tumor growth in animal models, validating this new receptor as a target for development of novel cancer therapeutics.

Abbreviations used: CXCL, chemokine ligand; CXCR, chemokine receptor; GPCR, G protein–coupled receptor; HUVEC, human umbilical vein endothelial cell; I-TAC, interferon-inducible T cell {alpha} chemoattractant; SDF-1, stromal cell–derived factor.

B.E. McMaster died on 17 May 2006.


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