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J. Biol. Chem., Vol. 279, Issue 43, 44606-44612, October 22, 2004

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Platelet-activating Factor-induced Chemokine Gene Expression Requires NF-B Activation and Ca²⁺/Calcineurin Signaling Pathways

INHIBITION BY RECEPTOR PHOSPHORYLATION AND -ARRESTIN RECRUITMENT^*

Rampura T. Venkatesha, Jasimuddin Ahamed, Christopher Nuesch, Asifa K. Zaidi, and Hydar Ali¶

From the Department of Pathology, University of Pennsylvania, School of Dental Medicine, Philadelphia, Pennsylvania 19104

Previously, we reported that platelet-activating factor (PAF) stimulates higher G protein activation and a more robust Ca²⁺ mobilization in RBL-2H3 cells expressing carboxyl terminus deletion, phosphorylation-deficient mutant of PAF receptor (mPAFR) when compared with the wild-type receptor (PAFR). However, PAF did not provide sufficient signal for CC chemokine receptor ligand 2 (CCL2) production in cells expressing mPAFR. Based on these findings, we hypothesized that receptor phosphorylation provides a G protein-independent signal that synergizes with Ca²⁺ mobilization to induce CCL2 production. Here, we show that a mutant of PAFR (D289A), which does not couple to G proteins, was resistant to agonist-induced receptor phosphorylation. Unexpectedly, we found that when this mutant was coexpressed with mPAFR, it restored NF-B activation and CCL2 production. PAF caused translocation of -arrestin from the cytoplasm to the membrane in cells expressing PAFR but not a phosphorylation-deficient mutant in which all Ser/Thr residues were replaced with Ala (ST-PAFR). Interestingly, PAF induced significantly higher NF-B and nuclear factor of activated T cells (NFAT)-luciferase activity as well as CCL2 production in cells expressing ST-PAFR than those expressing PAFR. Furthermore, a Ca²⁺/calcineurin inhibitor completely inhibited PAF-induced NFAT activation and CCL2 production but not NF-B activation. These findings suggest that the carboxyl terminus of PAFR provides a G protein-independent signal for NF-B activation, which synergizes with G protein-mediated Ca²⁺/calcineurin activation to induce CCL2 production. However, receptor phosphorylation and -arrestin recruitment inhibit CCL2 production by blocking both NF-B activation and Ca²⁺/calcineurin-dependent signaling pathways.

Received for publication, July 16, 2004

^* This work was supported by National Institutes of Health Grant HL-63372 and a American Heart Association Grant-in-Aid 0256361U. 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.

Present address: The Scripps Research Institute, 10550 Torrey Pines Rd., La Jolla, CA 92037.

^¶ To whom correspondence should be addressed: Dept. of Pathology, University of Pennsylvania School of Dental Medicine, 240 S. 40th St. (346 Levy Bldg.), Philadelphia, PA 19104-6002. Tel.: 215-573-1993; Fax: 215-573-2050; E-mail: ali{at}path.dental.upenn.edu.

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