The F-box protein beta-TrCP associates with phosphorylated beta-catenin and regulates its activity in the cell

Curr Biol. 1999 Feb 25;9(4):207-10. doi: 10.1016/s0960-9822(99)80091-8.


Defects in beta-catenin regulation contribute to the neoplastic transformation of mammalian cells. Dysregulation of beta-catenin can result from missense mutations that affect critical sites of phosphorylation by glycogen synthase kinase 3beta (GSK3beta). Given that phosphorylation can regulate targeted degradation of beta-catenin by the proteasome, beta-catenin might interact with an E3 ubiquitin ligase complex containing an F-box protein, as is the case for certain cell cycle regulators. Accordingly, disruption of the Drosophila F-box protein Slimb upregulates the beta-catenin homolog Armadillo. We reasoned that the human homologs of Slimb - beta-TrCP and its isoform beta-TrCP2 (KIAA0696) - might interact with beta-catenin. We found that the binding of beta-TrCP to beta-catenin was direct and dependent upon the WD40 repeat sequences in beta-TrCP and on phosphorylation of the GSK3beta sites in beta-catenin. Endogenous beta-catenin and beta-TrCP could be coimmunoprecipitated from mammalian cells. Overexpression of wild-type beta-TrCP in mammalian cells promoted the downregulation of beta-catenin, whereas overexpression of a dominant-negative deletion mutant upregulated beta-catenin protein levels and activated signaling dependent on the transcription factor Tcf. In contrast, beta-TrCP2 did not associate with beta-catenin. We conclude that beta-TrCP is a component of an E3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated beta-catenin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cadherins / metabolism
  • Carrier Proteins / metabolism
  • Cell Line
  • Cytoskeletal Proteins / chemistry
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • Drosophila
  • GTP-Binding Proteins / chemistry
  • GTP-Binding Proteins / metabolism*
  • Genes, Reporter
  • HeLa Cells
  • Humans
  • Phosphorylation
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Repetitive Sequences, Amino Acid
  • Trans-Activators*
  • Transfection
  • Ubiquitin-Protein Ligases
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins


  • BTRC protein, human
  • CTNNB1 protein, human
  • Cadherins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • FBXW11 protein, human
  • Protein Isoforms
  • Recombinant Proteins
  • Trans-Activators
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins
  • Ubiquitin-Protein Ligases
  • GTP-Binding Proteins