PP1 cooperates with ASPP2 to dephosphorylate and activate TAZ

J Biol Chem. 2011 Feb 18;286(7):5558-66. doi: 10.1074/jbc.M110.194019. Epub 2010 Dec 28.

Abstract

The Hippo pathway regulates organ size by controlling both cell proliferation and apoptosis. TAZ functions as a transcriptional co-activator downstream of the Hippo pathway and has been implicated in human cancer development. A key step in the Hippo-TAZ pathway is phosphorylation of TAZ by LATS kinase, which leads to TAZ inhibition by both cytoplasmic retention and degradation. However, the mechanism of TAZ dephosphorylation and the responsible phosphatase are unknown. Here, we identified PP1 as a bona fide TAZ phosphatase. PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. Furthermore, ASPP2 facilitates the interaction between TAZ and PP1 to promote TAZ dephosphorylation. As a result, PP1 and ASPP2 increase TAZ-dependent gene expression. This study demonstrates that PP1A and ASPP2 play a critical role in promoting TAZ function by antagonizing the LATS kinase through TAZ dephosphorylation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus / genetics
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Cell Nucleus / genetics
  • Cell Nucleus / metabolism*
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Phosphorylation / genetics
  • Protein Phosphatase 1 / genetics
  • Protein Phosphatase 1 / metabolism*
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins

Substances

  • Apoptosis Regulatory Proteins
  • Intracellular Signaling Peptides and Proteins
  • TP53BP2 protein, human
  • Trans-Activators
  • Transcription Factors
  • Transcriptional Coactivator with PDZ-Binding Motif Proteins
  • WWTR1 protein, human
  • PPP1CA protein, human
  • Protein Phosphatase 1