Combined functional genomic and proteomic approaches identify a PP2A complex as a negative regulator of Hippo signaling

Mol Cell. 2010 Aug 27;39(4):521-34. doi: 10.1016/j.molcel.2010.08.002.

Abstract

The Hippo (Hpo) pathway is a central determinant of tissue size in both Drosophila and higher organisms. The core of the pathway is a kinase cascade composed of an upstream kinase Hpo (MST1/2 in mammals) and a downstream kinase Warts (Wts, Lats1/2 in mammals), as well as several scaffold proteins, Sav, dRASSF, and Mats. Activation of the core kinase cassette results in phosphorylation and inactivation of the progrowth transcriptional coactivator Yki, leading to increased apoptosis and reduced tissue growth. The mechanisms that prevent inappropriate Hpo activation remain unclear, and in particular, the identity of the phosphatase that antagonizes Hpo is unknown. Using combined proteomic and RNAi screening approaches, we identify the dSTRIPAK PP2A complex as a major regulator of Hpo signaling. dSTRIPAK depletion leads to increased Hpo activatory phosphorylation and repression of Yki target genes in vivo, suggesting this phosphatase complex prevents Hpo activation during development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cell Proliferation
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / enzymology*
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Drosophila melanogaster / ultrastructure
  • Genomics* / methods
  • Genotype
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Multienzyme Complexes
  • Nuclear Proteins / metabolism
  • Phenotype
  • Phosphorylation
  • Protein Kinases / metabolism
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteomics* / methods
  • RNA Interference
  • Reproducibility of Results
  • Signal Transduction*
  • Tandem Mass Spectrometry
  • Trans-Activators / metabolism
  • Transfection

Substances

  • Carrier Proteins
  • Cell Cycle Proteins
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Multienzyme Complexes
  • Nuclear Proteins
  • RASSF protein, Drosophila
  • Trans-Activators
  • Yki protein, Drosophila
  • mts protein, Drosophila
  • sav protein, Drosophila
  • Protein Kinases
  • wts protein, Drosophila
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila
  • Protein Phosphatase 2