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MBC in Press, published online ahead of print March 28, 2007
Mol. Biol. Cell 10.1091/mbc.E06-09-0850

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Submitted on September 22, 2006
Revised on March 2, 2007
Accepted on March 16, 2007

PKC{alpha}-dependent Phosphorylation of the mRNA Stabilizing Factor HuR: Implications for Posttranscriptional Regulation of Cyclooxygenase-2

Anke Doller, Andrea Huwiler,* Roswitha Müller, Heinfried H. Radeke, Josef Pfeilschifter, and Wolfgang Eberhardt

Pharmazentrum Frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, 60590 Frankfurt am Main, Germany

Monitoring Editor: Marvin P. Wickens

In this study, we investigated the molecular mechanisms underlying the ATP analog adenosine 5'O-(thiotriphosphate) (ATP{gamma}S)-induced nucleo-cytoplasmic shuttling of the mRNA stabilizing factor HuR in human mesangial cells (hMC). Using synthetic protein kinase C (PKC) inhibitors and siRNA approaches we demonstrate that knock-down of PKC{alpha} efficiently blocked the ATP-dependent nuclear HuR export to the cytoplasm. The functional importance of PKC{alpha} in HuR shuttling is highlighted by the high cytosolic HuR content detected in hMC stably overexpressing PKC{alpha} when compared with mock-transfected cells. The ATP-induced recruitment of HuR to the cytoplasm is preceded by a direct interaction of PKC{alpha} with nuclear HuR and accompanied by increased Ser-phosphorylation as demonstrated by coimmunoprecipitation experiments. Mapping of putative PKC target sites identified serines 158 and 221 being indispensable for HuR-phosphorylation by PKC{alpha}. RNA pull-down assay and RNA EMSA demonstrated that the HuR shuttling by ATP is accompanied by an increased HuR-binding to COX-2 mRNA. Physiologically, the ATP-dependent increase in RNA binding is linked with an augmentation in COX-2 mRNA stability and subsequent increase in PGE2 synthesis. Regulation of HuR via PKC{alpha}-dependent phosphorylation emphasizes the importance of posttranslational modification for stimulus-dependent HuR shuttling.

*Present address: Institut für Pharmakologie, Universität Bern, CH-3010 Bern, Switzerland.

Address correspondence to: Wolfgang Eberhardt (w.eberhardt{at}em.uni-frankfurt.de)




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