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Nuclear HuR accumulation through phosphorylation by Cdk1

¹ Laboratory of Cellular and Molecular Biology, National Institute on Aging-Intramural Research Program, National Institutes of Health, Baltimore, Maryland 21224, USA; ² Department of Cellular and Molecular Pharmacology, University of California at San Francisco, San Francisco, California 94143, USA

A predominantly nuclear RNA-binding protein, HuR translocates to the cytoplasm in response to stress and proliferative signals, where it stabilizes or modulates the translation of target mRNAs. Here, we present evidence that HuR phosphorylation at S202 by the G2-phase kinase Cdk1 influences its subcellular distribution. HuR was specifically phosphorylated in synchronous G2-phase cultures; its cytoplasmic levels increased by Cdk1-inhibitory interventions and declined in response to Cdk1-activating interventions. In keeping with the prominently cytoplasmic location of the nonphosphorylatable point mutant HuR(S202A), phospho-HuR(S202) was shown to be predominantly nuclear using a novel anti-phospho-HuR(S202) antibody. The enhanced cytoplasmic presence of unphosphorylated HuR was linked to its decreased association with 14–3–3 and to its heightened binding to target mRNAs. Our findings suggest that Cdk1 phosphorylates HuR during G2, thereby helping to retain it in the nucleus in association with 14–3–3 and hindering its post-transcriptional function and anti-apoptotic influence.

[Keywords: RNA-binding protein; nucleocytoplasmic shuttling; 14–3–3 proteins; post-transcriptional gene regulation; cell division cycle; elav]

Received December 21, 2007; revised version accepted April 25, 2008.

E-MAIL myriam-gorospe{at}nih.gov; FAX (410) 558-8386.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1645808.

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