The hippo tumor pathway promotes TAZ degradation by phosphorylating a phosphodegron and recruiting the SCF{beta}-TrCP E3 ligase

J Biol Chem. 2010 Nov 26;285(48):37159-69. doi: 10.1074/jbc.M110.152942. Epub 2010 Sep 21.

Abstract

The TAZ transcription co-activator promotes cell proliferation and epithelial-mesenchymal transition. TAZ is inhibited by the Hippo tumor suppressor pathway, which promotes TAZ cytoplasmic localization by phosphorylation. We report here that TAZ protein stability is controlled by a phosphodegron recognized by the F-box protein β-TrCP and ubiquitylated by the SCF/CRL1(β-TrCP) E3 ligase. The interaction between TAZ and β-TrCP is regulated by the Hippo pathway. Phosphorylation of a phosphodegron in TAZ by LATS primes it for further phosphorylation by CK1ε and subsequent binding by β-TrCP. Therefore, the Hippo pathway negatively regulates TAZ function by both limiting its nuclear accumulation and promoting its degradation. The phosphodegron-mediated TAZ degradation plays an important role in negatively regulating TAZ biological functions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Casein Kinase I / genetics
  • Casein Kinase I / metabolism
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • NIH 3T3 Cells
  • Phosphorylation
  • Protein Binding
  • Protein Stability
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • SKP Cullin F-Box Protein Ligases / genetics
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Signal Transduction*
  • Trans-Activators
  • Transcription Factors

Substances

  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • Trans-Activators
  • Transcription Factors
  • WWTR1 protein, human
  • SKP Cullin F-Box Protein Ligases
  • LATS1 protein, human
  • Casein Kinase I
  • Protein-Serine-Threonine Kinases
  • hpo protein, Drosophila