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Cooperative regulation of extracellular signal-regulated kinase activation and cell shape change by filamin A and beta-arrestins.

Journal article
Authors Mark G H Scott
Vincenzo Pierotti
Hélène Storez
Erika Lindberg
Alain Thuret
Olivier Muntaner
Catherine Labbé-Jullié
Julie A Pitcher
Stefano Marullo
Published in Molecular and cellular biology
Volume 26
Issue 9
Pages 3432-45
ISSN 0270-7306
Publication year 2006
Published at Wallenberg Laboratory
Institute of Biomedicine, Department of Infectious Medicine
Pages 3432-45
Language en
Keywords Actins, metabolism, Amino Acid Sequence, Animals, Arrestins, analysis, genetics, metabolism, Binding Sites, Cell Membrane, chemistry, metabolism, Cell Shape, Cells, Cultured, Contractile Proteins, analysis, genetics, metabolism, Cytoskeletal Proteins, metabolism, Enzyme Activation, Humans, Immunoprecipitation, Microfilament Proteins, analysis, genetics, metabolism, Mitogen-Activated Protein Kinase 1, analysis, metabolism, Molecular Sequence Data, Protein Interaction Mapping, Protein Structure, Tertiary, genetics, Receptor, Angiotensin, Type 1, metabolism, Receptor, Muscarinic M1, metabolism, Repetitive Sequences, Amino Acid, genetics, Two-Hybrid System Techniques
Subject categories Medical and Health Sciences


beta-Arrestins (betaarr) 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 betaarr-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 betaarr-binding site involves tandem repeat 22 in the carboxyl terminus. betaarr binds FLNA through both its N- and C-terminal domains, indicating the presence of multiple binding sites. We demonstrate that betaarr 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 betaarr-ERK2 complex formation by FLNA. In Hep2 cells, stimulation of M1MR or AT1AR results in the colocalization of receptor, betaarr, FLNA, and active ERK in membrane ruffles. Reduction of endogenous levels of betaarr or FLNA and a catalytically inactive dominant negative MEK1, which prevents ERK activation, inhibit membrane ruffle formation, indicating the functional requirement for betaarr, FLNA, and active ERK in this process. Our results indicate that betaarr and FLNA cooperate to regulate ERK activation and actin cytoskeleton reorganization.

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