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Inhibition of LIMK activity by β‐arrestins: A mechanism for cofilin activation
Author(s) -
Lin Alice,
DeFea Kathryn
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.586.1
Subject(s) - cofilin , microbiology and biotechnology , g protein coupled receptor , phosphorylation , chemistry , actin remodeling , actin , actin cytoskeleton , biology , signal transduction , biochemistry , cytoskeleton , cell
β‐arrestins are mediators involved in activation and termination of GPCR signaling pathways without G‐protein coupling. Since ~40% of currently used therapeutics target GPCRs, it is important that our lab elucidate the role of β‐arrestins in protease‐activated‐receptor‐2‐induced actin reorganization. My project focuses on LIM kinase 1 (LIMK1), a key regulator of actin dynamics related to tumor cell invasion and metastasis, and dendritic spine formation through inhibiting the actin filament severing protein, cofilin. We have shown that LIMK1 directly interacts with β‐arrestin‐1(β1), and siRNA knockdown of β1 enhances both LIMK1 activity and the phosphorylation of cofilin. Here, we demonstrate the following 1) β1 directly binds LIMK and this primarily involves residues 164–418 of β1 and residues 285–638 of LIMK1, as determined by sandwich immunoassay and Bioluminescence Resonance Energy Transfer (BRET); 2) β1 directly binds and inhibits LIMK1 activity in vitro (as determined by cofilin phosphorylation), and 3) the inhibitory activity of β1 is mediated primarily through residues 1–163. These data suggest that β‐arrestins may facilitate cofilin activation by blocking the ability of LIMK to phosphorylate and inactivate cofilin. This represents a novel mechanism for the regulation of actin filament severing by β‐arrestins.