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Originally published as MBC in Press, 10.1091/mbc.E06-09-0850 on March 28, 2007

Vol. 18, Issue 6, 2137-2148, June 2007

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Protein Kinase C{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

Submitted September 22, 2006; Revised March 2, 2007; Accepted March 16, 2007
Monitoring Editor: Marvin P. Wickens

In this study, we investigated the molecular mechanisms underlying the ATP analogue adenosine-5'-O-(3-thio)triphosphate–induced nucleocytoplasmic shuttling of the mRNA stabilizing factor HuR in human (h) mesangial cells (MC). Using synthetic protein kinase C (PKC) inhibitors and small interfering RNA approaches, we demonstrated that knockdown 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} 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 as being indispensable for HuR phosphorylation by PKC{alpha}. RNA pull-down assay and RNA electrophoretic mobility shift assay demonstrated that the HuR shuttling by ATP is accompanied by an increased HuR binding to cyclooxygenase (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 prostaglandin E2 synthesis. Regulation of HuR via PKC{alpha}-dependent phosphorylation emphasizes the importance of posttranslational modification for stimulus-dependent HuR shuttling.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-09-0850) on March 28, 2007.

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

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

Abbreviations used: AMPK, AMP-activated kinase; ARE, adenosine uridine-rich element; COX, cyclooxygenase; ELAV, embryonic lethal abnormal vision; EMSA, electrophoretic mobility shift assay; MC, human mesangial cell(s); IL, interleukin; JNK, c-Jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; TNF, tumor necrosis factor; UTR, untranslated region.




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