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Protein phosphatase 1 dephosphorylates profilin-1 at Ser-137

Jieya Shao1, Marc I Diamond

  • 1Department of Neurology, School of Medicine, Washington University, St. Louis, Missouri, United States of America. shaoj@neuro.wustl.edu

Plos One
|April 6, 2012
PubMed

Insights

Protein phosphatase 1 (PP1) dephosphorylates Profilin-1 (PFN1) at Ser-137, activating its anti-aggregation function. This finding reveals a key regulatory mechanism for PFN1, a potential therapeutic target in diseases like Huntington's and cancer.

Area of Science:

  • Cellular biology
  • Biochemistry
  • Molecular medicine

Background:

  • Profilin-1 (PFN1) regulates actin dynamics and has roles in Huntington's disease and tumor suppression.
  • Rho-associated kinase (ROCK) phosphorylates PFN1 at Ser-137, inhibiting its anti-aggregation activity.
  • The specific phosphatase responsible for PFN1 dephosphorylation at Ser-137 was previously unknown.

Purpose of the Study:

  • To identify the phosphatase that dephosphorylates PFN1 at Ser-137, thereby activating its function.
  • To elucidate the regulatory mechanism of PFN1 phosphorylation and dephosphorylation.

Main Methods:

  • Utilized a phospho-specific antibody for Ser-137 PFN1.
  • Employed immunocytochemistry and plate reader-based assays in cultured cells.
  • Investigated the effects of phosphatase inhibitors (okadaic acid, endothall) and gene knockdown (PP1Cα, PP2ACα).

Main Results:

  • Okadaic acid and endothall increased pS137-PFN1 levels, consistent with Protein Phosphatase 1 (PP1) inhibition.
  • Knockdown of PP1 catalytic subunit alpha (PP1Cα), but not PP2A catalytic subunit alpha (PP2ACα), elevated pS137-PFN1 levels.
  • PP1Cα directly binds to PFN1, with increased interaction observed upon phosphomimetic mutation at Ser-137.

Conclusions:

  • Protein Phosphatase 1 (PP1) is identified as the primary phosphatase for PFN1 at Ser-137.
  • This study provides crucial mechanistic insights into the regulation of PFN1 activity through phosphorylation by ROCK and dephosphorylation by PP1.

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