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J. Biol. Chem., Vol. 283, Issue 8, 4943-4956, February 22, 2008

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Phosphorylation of the Human Retinoid X Receptor at Serine 260 Impairs Coactivator(s) Recruitment and Induces Hormone Resistance to Multiple Ligands^*

From the McGill University Health Centre, Montreal, Quebec H3A 1A1, Canada

The retinoid X receptor (RXR) is a member of the nuclear receptor superfamily that regulates transcription of target genes through heterodimerization with several partners, including peroxisome proliferator-activated receptor, retinoic acid receptor, thyroid receptor, and vitamin D receptor (VDR). We have shown previously that signaling through VDR·RXR heterodimers was attenuated in ras-transformed keratinocytes due to phosphorylation of serine 260 of the RXR via the activated Ras-Raf-MAPK cascade in these cells. In this study we demonstrate that phosphorylation at serine 260, a site located in the omega loop-AF-2 interacting domain of RXR, inhibits signaling through several heterodimeric partners of the RXR. The inhibition of signaling results in reduced transactivational response to ligand presentation and the reduced physiological response of growth inhibition not only of 1,25-dihydroxyvitamin D₃ but also of retinoic acid receptor ligands and LG1069 (an RXR ligand). This partial resistance to ligands could be reversed by inhibition of MAPK activity or by overexpression of a non-phosphorylable RXR mutant at serine 260 (RXR Ser-260 Ala). Importantly, phosphorylation of RXR at serine 260 impaired the recruitment of DRIP205 and other coactivators to the VDR·RXR complex. Chromatin immunoprecipitation and pulldown assays further demonstrated that coactivator recruitment to the VDR·RXR complex could be restored by treatment with a MAPK inhibitor. Our data suggest that phosphorylation at serine 260 plays a critical role in inducing hormone resistance of RXR-mediated signaling likely through structural changes in the H₁-H₃ omega loop-AF2 coactivator(s) interacting domain.

Received for publication, September 7, 2007 , and in revised form, November 13, 2007.

^* This work was supported by an operating grant (MT10839 to R. K.) from the Canadian Institutes of Health Research. 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 To whom correspondence should be addressed: McGill University Health Centre, 687 Pine Ave. W., Rm. H4.67, Montreal, Quebec H3A 1A1, Canada. Tel.: 514-843-1632; Fax: 514-843-1712; E-mail: Richard.kremer{at}mcgill.ca.

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