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Molecular and Cellular Biology, February 2007, p. 803-817, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.00601-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Interaction with MEK Causes Nuclear Export and Downregulation of Peroxisome Proliferator-Activated Receptor {gamma}{triangledown}

Elke Burgermeister,1,{dagger} Dana Chuderland,1 Tamar Hanoch,1 Markus Meyer,2 Mordechai Liscovitch,1 and Rony Seger1*

Department of Biological Regulation, The Weizmann Institute of Science, 76100 Rehovot, Israel,1 Department of Exploratory Development, Pharmaceuticals Division, Fa. Hoffmann-La Roche AG, Grenzacher Strasse 124, CH-4070 Basel, Switzerland2

Received 7 April 2006/ Returned for modification 5 May 2006/ Accepted 3 November 2006

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade plays a central role in intracellular signaling by many extracellular stimuli. One target of the ERK cascade is peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), a nuclear receptor that promotes differentiation and apoptosis. It was previously demonstrated that PPAR{gamma} activity is attenuated upon mitogenic stimulation due to phosphorylation of its Ser84 by ERKs. Here we show that stimulation by tetradecanoyl phorbol acetate (TPA) attenuates PPAR{gamma}'s activity in a MEK-dependent manner, even when Ser84 is mutated to Ala. To elucidate the mechanism of attenuation, we found that PPAR{gamma} directly interacts with MEKs, which are the activators of ERKs, but not with ERKs themselves, both in vivo and in vitro. This interaction is facilitated by MEKs' phosphorylation and is mediated by the basic D domain of MEK1 and the AF2 domain of PPAR{gamma}. Immunofluorescence microscopy and subcellular fractionation revealed that MEK1 exports PPAR{gamma} from the nucleus, and this finding was supported by small interfering RNA knockdown of MEK1 and use of a cell-permeable interaction-blocking peptide, which prevented TPA-induced export of PPAR{gamma} from the nucleus. Thus, we show here a novel mode of downregulation of PPAR{gamma} by its MEK-dependent redistribution from the nucleus to the cytosol. This unanticipated role for the stimulation-induced nuclear shuttling of MEKs shows that MEKs can regulate additional signaling components besides the ERK cascade.

* Corresponding author. Mailing address: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel. Phone: 972 8 9343602. Fax: 972 8 9344116. E-mail: rony.seger{at}weizmann.ac.il.

{triangledown} Published ahead of print on 13 November 2006.

{dagger} Present address: Dept. of Internal Medicine II, Technical University of Munich, Ismaningerstr 22, D-81675 Munich, Germany.

Molecular and Cellular Biology, February 2007, p. 803-817, Vol. 27, No. 3
0270-7306/07/$08.00+0     doi:10.1128/MCB.00601-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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