The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin

Oncogene. 1999 Jan 28;18(4):849-54. doi: 10.1038/sj.onc.1202653.

Abstract

Ubiquitin-conjugation targets numerous cellular regulators for proteasome-mediated degradation. Thus, the identification of ubiquitin ligases and their physiological substrates is crucially important, especially for those cases in which aberrant levels of regulatory proteins (e.g., beta-catenin, p27) result from a deregulated ubiquitination pathway. In yeast, the proteolysis of several G1 regulators is controlled by ubiquitin ligases (or SCFs) formed by three subunits: Skp1, Cul A (Cdc53), and one of many F-box proteins. Specific F-box proteins (Fbps) recruit different substrates to the SCF. Although many Fbps have been identified in mammals, their specific substrates and the existence of multiple SCFs have not yet been reported. We have found that one human Fbp, beta-Trcp (beta-Transducin repeat containing protein), does indeed form a novel SCF with human Skp1 and Cul1. Consistent with recent reports indicating that Xenopus and Drosophila beta-Trcp homologs act as negative regulators of the Wnt/beta-catenin signaling pathway, we report here that human beta-Trcp interacts with beta-catenin in vivo. Furthermore, beta-catenin is specifically stabilized in vivo by the expression of a dominant negative beta-Trcp. These results indicate that the Cul1/Skp1/beta-Trcp complex forms a ubiquitin ligase that mediates the degradation of beta-catenin.

Publication types

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

MeSH terms

  • CD4 Antigens / metabolism
  • Cell Cycle Proteins / metabolism*
  • Cells, Cultured
  • Cytoskeletal Proteins / metabolism*
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Ligases / metabolism*
  • S-Phase Kinase-Associated Proteins
  • Substrate Specificity
  • Trans-Activators*
  • Ubiquitins / metabolism
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins

Substances

  • BTRC protein, human
  • CD4 Antigens
  • CTNNB1 protein, human
  • Cell Cycle Proteins
  • Cytoskeletal Proteins
  • S-Phase Kinase-Associated Proteins
  • Trans-Activators
  • Ubiquitins
  • beta Catenin
  • beta-Transducin Repeat-Containing Proteins
  • GTP-Binding Proteins
  • Ligases