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Par-4: a new activator of myosin phosphatase.

Authors: Vetterkind, S  Lee, E  Sundberg, E  Poythress, RH  Tao, TC  Preuss, U  Morgan, KG 
Citation: Vetterkind S, etal., Mol Biol Cell. 2010 Apr 1;21(7):1214-24. doi: 10.1091/mbc.E09-08-0711. Epub 2010 Feb 3.
Pubmed: (View Article at PubMed) PMID:20130087
DOI: Full-text: DOI:10.1091/mbc.E09-08-0711

Myosin phosphatase (MP) is a key regulator of myosin light chain (LC20) phosphorylation, a process essential for motility, apoptosis, and smooth muscle contractility. Although MP inhibition is well studied, little is known about MP activation. We have recently demonstrated that prostate apoptosis response (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, whereas small interfering RNA knockdown 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 in which 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.

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CRRD Object Information
CRRD ID: 9835415
Created: 2015-03-25
Species: All species
Last Modified: 2015-03-25
Status: ACTIVE



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