HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900269v1 183/5/3204    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Zabel, B. A. Articles by Schall, T. J. PubMed PubMed Citation Articles by Zabel, B. A. Articles by Schall, T. J.

Elucidation of CXCR7-Mediated Signaling Events and Inhibition of CXCR4-Mediated Tumor Cell Transendothelial Migration by CXCR7 Ligands

Brian A. Zabel^1,*, Yu Wang^*, Susanna Lewén^*, Robert D. Berahovich^*, Mark E. T. Penfold^*, Penglie Zhang^*, Jay Powers^*, Bretton C. Summers^*, Zhenhua Miao^*, Bin Zhao^*, Ali Jalili, Anna Janowska-Wieczorek, Juan C. Jaen^* and Thomas J. Schall^*

^* ChemoCentryx, Mountain View, CA 94043; and Division of Clinical Hematology, Medicine, University of Alberta, Edmonton, Alberta, Canada

CXCR7 binds chemokines CXCL11 (I-TAC) and CXCL12 (SDF-1) but does not act as a classical chemoattractant receptor. Using CCX771, a novel small molecule with high affinity and selectivity for CXCR7, we found that, although CXCR7 is dispensable for "bare filter" in vitro chemotaxis, CXCR7 plays an essential role in the CXCL12/CXCR4-mediated transendothelial migration (TEM) of CXCR4⁺CXCR7⁺ human tumor cells. Importantly, although CXCL11 is unable to stimulate directly the migration of these cells, it acts as a potent antagonist of their CXCL12-induced TEM. Furthermore, even though this TEM is driven by CXCR4, the CXCR7 ligand CCX771 is substantially more potent at inhibiting it than the CXCR4 antagonist AMD3100, which is more than 100 times weaker at inhibiting TEM when compared with its ability to block bare filter chemotaxis. Far from being a "silent" receptor, we show that CXCR7 displays early hallmark events associated with intracellular signaling. Upon cognate chemokine binding, CXCR7 associates with β-arrestin2, an interaction that can be blocked by CXCR7-specific mAbs. Remarkably, the synthetic CXCR7 ligand CCX771 also potently stimulates β-arrestin2 recruitment to CXCR7, with greater potency and efficacy than the endogenous chemokine ligands. These results indicate that CXCR7 can regulate CXCL12-mediated migratory cues, and thus may play a critical role in driving CXCR4⁺CXCR7⁺ tumor cell metastasis and tissue invasion. CXCR7 ligands, such as the chemokine CXCL11 and the newly described synthetic molecule CCX771, may represent novel therapeutic opportunities for the control of such cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Brian A. Zabel, ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, CA 94043. E-mail address: bzabel{at}chemocentryx.com

² Abbreviations used in this paper: TEM, transendothelial migration; β-gal, β-galactosidase; GPCR, G protein-coupled receptor; CHO, Chinese hamster ovary.

³ The online version of this article contains supplemental material.