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Molecular and Cellular Biology, October 2004, p. 8691-8704, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8691-8704.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor {gamma}1 (PPAR{gamma}1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPAR{gamma}1 Transcriptional Activation: Involvement in Flow-Induced PPAR{gamma} Activation in Endothelial Cells

Masashi Akaike,{dagger} Wenyi Che,{dagger} Nicole-Lerner Marmarosh, Shinsuke Ohta, Masaki Osawa, Bo Ding, Bradford C. Berk, Chen Yan, and Jun-ichi Abe*

Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Rochester, New York

Received 25 March 2004/ Returned for modification 29 April 2004/ Accepted 12 July 2004

Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that form a subfamily of the nuclear receptor gene family. Since both flow and PPAR{gamma} have atheroprotective effects and extracellular signal-regulated kinase 5 (ERK5) kinase activity is significantly increased by flow, we investigated whether ERK5 kinase regulates PPAR{gamma} activity. We found that activation of ERK5 induced PPAR{gamma}1 activation in endothelial cells (ECs). However, we could not detect PPAR{gamma} phosphorylation by incubation with activated ERK5 in vitro, in contrast to ERK1/2 and JNK, suggesting a role for ERK5 as a scaffold. Endogenous PPAR{gamma}1 was coimmunoprecipitated with endogenous ERK5 in ECs. By mammalian two-hybrid analysis, we found that PPAR{gamma}1 associated with ERK5a at the hinge-helix 1 region of PPAR{gamma}1. Expressing a hinge-helix 1 region PPAR{gamma}1 fragment disrupted the ERK5a-PPAR{gamma}1 interaction, suggesting a critical role for hinge-helix 1 region of PPAR{gamma} in the ERK5-PPAR{gamma} interaction. Flow increased ERK5 and PPAR{gamma}1 activation, and the hinge-helix 1 region of the PPAR{gamma}1 fragment and dominant negative MEK5ß significantly reduced flow-induced PPAR{gamma} activation. The dominant negative MEK5ß also prevented flow-mediated inhibition of tumor necrosis factor alpha-mediated NF-{kappa}B activation and adhesion molecule expression, including vascular cellular adhesion molecule 1 and E-selectin, indicating a physiological role for ERK5 and PPAR{gamma} activation in flow-mediated antiinflammatory effects. We also found that ERK5 kinase activation was required, likely by inducing a conformational change in the NH2-terminal region of ERK5 that prevented association of ERK5 and PPAR{gamma}1. Furthermore, association of ERK5a and PPAR{gamma}1 disrupted the interaction of SMRT and PPAR{gamma}1, thereby inducing PPAR{gamma} activation. These data suggest that ERK5 mediates flow- and ligand-induced PPAR{gamma} activation via the interaction of ERK5 with the hinge-helix 1 region of PPAR{gamma}.

* Corresponding author. Mailing address: Center for Cardiovascular Research, 601 Elmwood Ave., Box 679, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642. Phone: (585) 273-1686. Fax: (585) 275-9895. E-mail: jun-chi_abe{at}urmc.rochester.edu.

{dagger} M.A. and W.C. contributed equally to this work.

Molecular and Cellular Biology, October 2004, p. 8691-8704, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8691-8704.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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