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MBC in Press, published online ahead of print February 3, 2010
Mol. Biol. Cell 10.1091/mbc.E09-08-0711

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Submitted on August 19, 2009
Revised on January 21, 2010
Accepted on January 26, 2010

Par-4: A New Activator of Myosin Phosphatase

Susanne Vetterkind,* Eunhee Lee,{dagger} Eric Sundberg,{dagger} Ransom H. Poythress,* Terence C. Tao,{dagger} Ute Preuss,{ddagger} and Kathleen G. Morgan*

*Department of Health Sciences, Sargent College of Health and Rehabilitation Sciences, Boston University, Boston, MA 02215; {dagger}Boston Biomedical Research Institute, Watertown, MA 02472; {ddagger}Institute of Genetics, University of Bonn, D-53117 Bonn, Germany

Monitoring Editor: Mark H. Ginsberg

Myosin phosphatase (MP) is a key regulator of myosin light chain (LC20) phosphorylation, a process essential for motility, apoptosis and smooth muscle contractility. While MP inhibition is well studied, little is known about MP activation. We have recently demonstrated that prostate apoptosis response-4 (Par-4) modulates vascular smooth muscle contractility. Here, we test the hypothesis that Par-4 regulates MP activity directly. We show, by proximity ligation assays, surface plasmon resonance and coimmunoprecipitation, that Par-4 interacts with the targeting subunit of MP, MYPT1. Binding is mediated by the leucine zippers of MYPT1 and Par-4, and reduced by Par-4 phosphorylation. Overexpression of Par-4 leads to increased phosphatase activity of immunoprecipitated MP, while siRNA knock down of endogenous Par-4 significantly decreases MP activity and increases MYPT1 phosphorylation. LC20 phosphorylation assays demonstrate that overexpression of Par-4 reduces LC20 phosphorylation. In contrast, a phosphorylation site mutant, but not wild-type Par-4, interferes with zipper-interacting protein kinase (ZIPK)-mediated MP inhibition. We conclude from our results Par-4 operates through a "padlock" model where binding of Par-4 to MYPT1 activates MP by blocking access to the inhibitory phosphorylation sites, and inhibitory phosphorylation of MYPT1 by ZIPK requires "unlocking" of Par-4 by phosphorylation and displacement of Par-4 from the MP complex.

Address correspondence to: Kathleen G. Morgan (kmorgan{at}bu.edu)






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