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J. Biol. Chem., Vol. 279, Issue 29, 30219-30227, July 16, 2004

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Intracellular Domains of CXCR3 That Mediate CXCL9, CXCL10, and CXCL11 Function^*

Richard A. Colvin, Gabriele S. V. Campanella, Jieti Sun, and Andrew D. Luster

From the Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston, Massachusetts 02129

The chemokine receptor CXCR3 is a G protein-coupled receptor found predominantly on T cells that is activated by three ligands as follows: CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC). Previously, we have found that of the three ligands, CXCL11 is the most potent inducer of CXCR3 internalization and is the physiologic inducer of CXCR3 internalization after T cell contact with activated endothelial cells. We have therefore hypothesized that these three ligands transduce different signals to CXCR3. In light of this hypothesis, we sought to determine whether regions of CXCR3 are differentially required for CXCL9, CXCL10, and CXCL11 function. Here we identified two distinct domains that contributed to CXCR3 internalization. The carboxyl-terminal domain and -arrestin1 were predominantly required by CXCL9 and CXCL10, and the third intracellular loop was predominantly required by CXCL11. Chemotaxis and calcium mobilization induced by all three CXCR3 ligands were dependent on the CXCR3 carboxyl terminus and the DRY sequence in the third trans-membrane domain. Our findings demonstrate that distinct domains of CXCR3 mediate its functions and suggest that the differential requirement of these domains contributes to the complexity of the chemokine system.

Received for publication, March 31, 2004 , and in revised form, May 7, 2004.

^* This work was supported by National Institutes of Health Grants K08 AI50147 (to R. A. C.), PO1 DK50305, and R01 CA69212 (to A. D. L.). 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.

To whom correspondence should be addressed: Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, 149 Thirteenth St., Rm. 8031, Charlestown, MA 02129. Tel.: 617-726-5710; Fax: 617-726-5651; E-mail: aluster{at}partners.org.

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