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Molecular and Cellular Biology, May 2006, p. 3432-3445, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3432-3445.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cooperative Regulation of Extracellular Signal-Regulated Kinase Activation and Cell Shape Change by Filamin A and ß-Arrestins

Mark G. H. Scott,1,2* Vincenzo Pierotti,1 Hélène Storez,1 Erika Lindberg,1,{dagger} Alain Thuret,1 Olivier Muntaner,1 Catherine Labbé-Jullié,1 Julie A. Pitcher,2,§ and Stefano Marullo1,§

Department of Cell Biology, Institut Cochin (INSERM U567, CNRS UMR 8104, Université Paris 5), 27 rue du Faubourg St Jacques, 75014 Paris, France,1 MRC Laboratory for Molecular Cell Biology and Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, United Kingdom2

Received 10 June 2005/ Returned for modification 9 August 2005/ Accepted 15 February 2006

ß-Arrestins (ßarr) are multifunctional adaptor proteins that can act as scaffolds for G protein-coupled receptor activation of mitogen-activated protein kinases (MAPK). Here, we identify the actin-binding and scaffolding protein filamin A (FLNA) as a ßarr-binding partner using Son of sevenless recruitment system screening, a classical yeast two-hybrid system, coimmunoprecipitation analyses, and direct binding in vitro. In FLNA, the ßarr-binding site involves tandem repeat 22 in the carboxyl terminus. ßarr binds FLNA through both its N- and C-terminal domains, indicating the presence of multiple binding sites. We demonstrate that ßarr and FLNA act cooperatively to activate the MAPK extracellular signal-regulated kinase (ERK) downstream of activated muscarinic M1 (M1MR) and angiotensin II type 1a (AT1AR) receptors and provide experimental evidence indicating that this phenomenon is due to the facilitation of ßarr-ERK2 complex formation by FLNA. In Hep2 cells, stimulation of M1MR or AT1AR results in the colocalization of receptor, ßarr, FLNA, and active ERK in membrane ruffles. Reduction of endogenous levels of ßarr or FLNA and a catalytically inactive dominant negative MEK1, which prevents ERK activation, inhibit membrane ruffle formation, indicating the functional requirement for ßarr, FLNA, and active ERK in this process. Our results indicate that ßarr and FLNA cooperate to regulate ERK activation and actin cytoskeleton reorganization.

* Corresponding author. Mailing address: Institut Cochin, Dept. of Cell Biology, 27 rue du Faubourg St Jacques, 75014 Paris, France. Phone: 33 1 40 51 65 48. Fax: 33 1 40 51 65 50. E-mail: scott{at}cochin.inserm.fr.

{dagger} Present address: Wallenberg Laboratory, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden.

§ These authors contributed equally to this work.

Molecular and Cellular Biology, May 2006, p. 3432-3445, Vol. 26, No. 9
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.9.3432-3445.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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