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

M. Hart, J. P. Concordet, I. Lassot, I. Albert, R. Del Los Santos, H. Durand, C. Perret, B. Rubinfeld, F. Margottin, R. Benarous, P. Polakis

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524 Scopus citations

Abstract

Defects in β-catenin regulation contribute to the neoplastic transformation of mammalian cells. Dysregulation of β-catenin can result from missense mutations that affect critical sites of phosphorylation by glycogen synthase kinase 3β (GSK3β). Given that phosphorylation can regulate targeted degradation of β-catenin by the proteasome, β-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 β-catenin homolog Armadillo. We reasoned that the human homologs of Slimb β-TrCP and its isoform β-TrCP2 (KIAA0696) - might interact with β-catenin. We found that the binding of β-TrCP to β-catenin was direct and dependent upon the WD40 repeat sequences in β-TrCP and on phosphorylation of the GSK3β sites in β-catenin. Endogenous β-catenin and β-TrCP could be coimmunoprecipitated from mammalian cells. Overexpression of wild-type β-TrCP in mammalian cells promoted the downregulation of β-catenin, whereas overexpression of a dominant-negative deletion mutant upregulated β-catenin protein levels and activated signaling dependent on the transcription factor Tcf. In contrast, β-TrCP2 did not associate with β-catenin. We conclude that β-TrCP is a component of an E3 ubiquitin ligase that is responsible for the targeted degradation of phosphorylated β-catenin.

Original languageEnglish (US)
Pages (from-to)207-211
Number of pages5
JournalCurrent Biology
Volume9
Issue number4
DOIs
StatePublished - Feb 25 1999
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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    Hart, M., Concordet, J. P., Lassot, I., Albert, I., Del Los Santos, R., Durand, H., Perret, C., Rubinfeld, B., Margottin, F., Benarous, R., & Polakis, P. (1999). The F-box protein β-TrCP associates with phosphorylated β-catenin and regulates its activity in the cell. Current Biology, 9(4), 207-211. https://doi.org/10.1016/S0960-9822(99)80091-8