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Molecular and Cellular Biology, October 2008, p. 6302-6313, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00427-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Serum-Induced Phosphorylation of the Serum Response Factor Coactivator MKL1 by the Extracellular Signal-Regulated Kinase 1/2 Pathway Inhibits Its Nuclear Localization{triangledown}

Susanne Muehlich, Ruigong Wang,{dagger} Seung-Min Lee, Thera C. Lewis, Chao Dai, and Ron Prywes*

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

Received 14 March 2008/ Returned for modification 8 May 2008/ Accepted 29 July 2008

Megakaryoblastic leukemia 1 (MKL1) is a myocardin-related coactivator of the serum response factor (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 mitogen-activated protein kinase phosphorylation site, and its modification was blocked by the MEK1 inhibitor U0126, implying that extracellular signal-regulated kinase 1/2 (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 MKL1 is then downregulated by nuclear export due to ERK1/2 phosphorylation.

* Corresponding author. Mailing address: Department of Biological Sciences, Columbia University, Fairchild 813B, MC 2420, 1212 Amsterdam Avenue, New York, NY 10027. Phone: (212) 854-8281. Fax: (212) 854-7655. E-mail: mrp6{at}columbia.edu

{triangledown} Published ahead of print on 11 August 2008.

{dagger} Present address: Advanced Vision Therapies, Inc., 9 W Watkins Mill Road, Suite 250, Gaithersburg, MD 20878.

Molecular and Cellular Biology, October 2008, p. 6302-6313, Vol. 28, No. 20
0270-7306/08/$08.00+0     doi:10.1128/MCB.00427-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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