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J. Biol. Chem., Vol. 279, Issue 31, 32524-32533, July 30, 2004

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The CXC Chemokine Receptor Encoded by Herpesvirus saimiri, ECRF3, Shows Ligand-regulated Signaling through G_i, G_q, and G_12/13 Proteins but Constitutive Signaling Only through G_i and G_12/13 Proteins^*

Mette M. Rosenkilde, Katherine A. McLean, Peter J. Holst, and Thue W. Schwartz

From the Laboratory for Molecular Pharmacology, Department of Pharmacology, the Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark

Open reading frame 74 (ORF74) of many ₂ -herpesviruses encodes a CXC chemokine receptor. The molecular pharmacological profile of ORF74 from herpesvirus saimiri, ECRF3, is characterized here and compared with that of the well known ORF74 from human herpesvirus 8 (HHV8). The ECRF3 receptor bound the so-called ELR (Glu-Leu-Arg) CXC chemokines ¹²⁵I-CXCL1/GRO, ¹²⁵I-CXCL6/GCP-2, and ¹²⁵I-CXCL8/interleukin-8 with high affinity; but in contrast to ORF74 from HHV8, it did not bind the non-ELR CXC chemokine ¹²⁵I-CXCL10/IP10. Interestingly, the B_max value for CXCL6/GCP-2 was 3-fold higher than the capacity for maximal binding of CXCL1/GRO to ECRF3 and 85-fold higher than that of CXCL8/interleukin-8, despite similar affinities. Like ORF74 from HHV8, ECRF3 activated a broad range of pathways (G_q, G_i, and G_12/13 as well as the cAMP response element-binding protein, NF-B, NFAT, and serum response element transcription factors) in a ligand-regulated manner, with CXCL6/GCP-2 being the most potent and efficacious agonist. ECRF3 signaled constitutively through G_i and G_12/13, but surprisingly not through G_q. At the level of transcription factor activation, the serum response element was activated constitutively by ECRF3, whereas cAMP response element-binding protein, NFAT, and NF-B were only ligand-regulated. The maximal signaling capacities were similar for the two receptors; however, the ligand-regulated signaling was responsible for the major part of the total ECRF3 signaling and only for a minor part of the total HHV8 ORF74 signaling. The activation pattern of ECRF3 with constitutive activation of some (but not all) of the employed pathways has not been seen before in endogenous or virus-encoded chemokine receptors. The results suggest that the unique ligand selectivity of ECRF3 among ORF74 receptors could reflect differences in the cellular tropism of the ₂-herpesviruses.

Received for publication, December 8, 2003 , and in revised form, May 14, 2004.

^* This work was supported by grants from the Danish Medical Council, the Danish Cancer Foundation, and the NovoNordisk Foundation. 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: Lab. for Molecular Pharmacology, Dept. of Pharmacology, Panum Inst., Bldg. 18.6, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark. Tel.: 45-3532-7608; Fax: 45-3532-7610; E-mail: rosenkilde{at}molpharm.dk.

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