A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF(beta-TRCP)

Genes Dev. 2010 Jan 1;24(1):72-85. doi: 10.1101/gad.1843810.

Abstract

The Yes-associated protein (YAP) transcription coactivator is a key regulator of organ size and a candidate human oncogene. YAP is inhibited by the Hippo pathway kinase cascade, at least in part via phosphorylation of Ser 127, which results in YAP 14-3-3 binding and cytoplasmic retention. Here we report that YAP is phosphorylated by Lats on all of the five consensus HXRXXS motifs. Phosphorylation of Ser 381 in one of them primes YAP for subsequent phosphorylation by CK1delta/epsilon in a phosphodegron. The phosphorylated phosphodegron then recruits the SCF(beta-TRCP) E3 ubiquitin ligase, which catalyzes YAP ubiquitination, ultimately leading to YAP degradation. The phosphodegron-mediated degradation and the Ser 127 phosphorylation-dependent translocation coordinately suppress YAP oncogenic activity. Our study identified CK1delta/epsilon as new regulators of YAP and uncovered an intricate mechanism of YAP regulation by the Hippo pathway via both S127 phosphorylation-mediated spatial regulation (nuclear-cytoplasmic shuttling) and the phosphodegron-mediated temporal regulation (degradation).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Amino Acid Motifs
  • Casein Kinase I / metabolism*
  • Cell Line
  • Gene Expression Regulation*
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mutation
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Protein Stability
  • Protein-Serine-Threonine Kinases / metabolism*
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Serine / metabolism
  • Transcription Factors
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Intracellular Signaling Peptides and Proteins
  • Phosphoproteins
  • Transcription Factors
  • YAP1 (Yes-associated) protein, human
  • Serine
  • SKP Cullin F-Box Protein Ligases
  • LATS1 protein, human
  • Casein Kinase I
  • Protein-Serine-Threonine Kinases