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Mol. Cell. Biol. doi:10.1128/MCB.00427-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Serum-induced phosphorylation of the SRF coactivator MKL1 by the ERK1/2 pathway inhibits its nuclear localization

Department of Biological Sciences, Columbia University, New York 10027, USA

^* To whom correspondence should be addressed. Email: mrp6{at}columbia.edu.

	Abstract

MKL1 is a myocardin-related coactivator of the SRF transcription factor which has an integral role in differentiation, migration and proliferation. Serum induces RhoA-dependent translocation of MKL1 from the cytoplasm to the nucleus and also causes a rapid increase in MKL1 phosphorylation. We have mapped a serum-inducible phosphorylation site and found, surprisingly, that its mutation causes constitutive localization to the nucleus suggesting that phosphorylation of MKL1 inhibits its serum-induced nuclear localization. The key site, Serine 454, resembles a MAPK phosphorylation site and its modification was blocked by the MEK1 inhibitor U0126, implying that ERK1/2 is the serum-inducible kinase that phosphorylates MKL1. Previous results indicated that G-actin binding to MKL1 promotes its nuclear export and we found that MKL1 phosphorylation is required for its binding to actin, explaining its effect on localization. We propose a model in which serum induction initially stimulates MKL1 nuclear localization due to a decrease in G-actin levels, but that MKL1 is then down regulated by nuclear export due to ERK1/2 phosphorylation.