APC is essential for targeting phosphorylated beta-catenin to the SCFbeta-TrCP ubiquitin ligase

Mol Cell. 2008 Dec 5;32(5):652-61. doi: 10.1016/j.molcel.2008.10.023.


Ubiquitin-dependent proteolysis is an important mechanism that suppresses the beta-catenin transcription factor in cells without Wnt stimulation. A critical step in this regulatory pathway is to create a SCF(beta-TrCP) E3 ubiquitin ligase binding site for beta-catenin. Here we show that the SCF(beta-TrCP) binding site created by phosphorylation of beta-catenin is highly vulnerable to protein phosphatase 2A (PP2A) and must be protected by the adenomatous polyposis coli (APC) tumor suppressor protein. Specifically, phosphorylated beta-catenin associated with the wild-type APC protein is recruited to the SCF(beta-TrCP) complex, ubiquitin conjugated, and degraded. A mutation in APC that deprives this protective function exposes the N-terminal phosphorylated serine/threonine residues of beta-catenin to PP2A. Dephosphorylation at these residues by PP2A eliminates the SCF(beta-TrCP) recognition site and blocks beta-catenin ubiquitin conjugation. Thus, by acting to protect the E3 ligase binding site, APC ensures the ubiquitin conjugation of phosphorylated beta-catenin.

Publication types

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

MeSH terms

  • Adenomatous Polyposis Coli Protein / chemistry
  • Adenomatous Polyposis Coli Protein / metabolism*
  • Animals
  • Binding Sites
  • Cell Line, Tumor
  • Cell Membrane / metabolism
  • Humans
  • Mutation / genetics
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Phosphatase 2 / deficiency
  • Protein Phosphatase 2 / metabolism
  • Protein Processing, Post-Translational
  • Protein Transport
  • SKP Cullin F-Box Protein Ligases / metabolism*
  • Substrate Specificity
  • Ubiquitin / metabolism
  • Ubiquitination
  • Xenopus
  • beta Catenin / metabolism*
  • beta-Transducin Repeat-Containing Proteins / metabolism*


  • Adenomatous Polyposis Coli Protein
  • BTRC protein, human
  • CTNNB1 protein, human
  • Phosphoproteins
  • Ubiquitin
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins
  • SKP Cullin F-Box Protein Ligases
  • Protein Phosphatase 2