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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900894v1 183/5/3268    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 Wang, A. Articles by Osborne, B. A. PubMed PubMed Citation Articles by Wang, A. Articles by Osborne, B. A.

Phosphorylation of Nur77 by the MEK-ERK-RSK Cascade Induces Mitochondrial Translocation and Apoptosis in T Cells¹

Aibo Wang^*, Jonathan Rud, Chris M. Olson, Jr.^*, Juan Anguita^*, and Barbara A. Osborne^2,*,

^* Department of Veterinary and Animal Sciences, University of Massachusetts MA 01003; and Program of Molecular and Cellular Biology, University of Massachusetts MA 01003

Nur77, an orphan nuclear receptor, plays a key role in apoptosis in T cells. In cancer cell lines, Nur77 can induce apoptosis through the intrinsic apoptotic pathway, but the mechanism by which Nur77 kills T cells remains controversial. In this study, we provide biochemical, pharmacological, and genetic evidence demonstrating that Nur77 induces apoptosis through the activation of the intrinsic pathway in T cells. We also show that Nur77 is a physiological substrate of the MEK-ERK-RSK cascade. Specifically, we demonstrate that RSK phosphorylates Nur77 at serine 354 and this modulates Nur77 nuclear export and intracellular translocation during T cell death. Our data reveal that Nur77 phosphorylation and mitochondrial targeting, regulated by RSK, defines a role for the MEK1/2-ERK1/2 cascade in T cell apoptosis.

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 This study was supported by a grant from NIH AI049361 (to B.A.O.).

² Address correspondence and reprint requests to Dr. Barbara Osborne, University of Massachusetts, 311 Paige Laboratory, Box 36410, Amherst, MA 01003-6410. E-mail address: osborne{at}vasci.umass.edu

³ Abbreviations used in this paper: DP, double positive; RSK, ribosomal protein S6 kinase; PNS, postnuclear supernatant; P+I, PMA plus ionomycin; NES, nuclear export sequence; WT, wild type; FCCP, p-trifluoromethoxy carbonyl cyanide phenyl hydrazone; NWB, nuclear wash buffer; PARP, poly (ADP-ribose) polymerase; TMRE, tetramethylrhodamine, ethyl ester, perchlorate; MW, molecular weight.

⁴ The online version of this article contains supplemental material.