Fas-associated Factor 1 Is a Scaffold Protein That Promotes beta-Transducin Repeat-containing Protein (beta-TrCP)-mediated beta-Catenin Ubiquitination and Degradation

Long Zhang, Fangfang Zhou*, Yihao Li, Yvette Drabsch, Juan Zhang, Hans van Dam, Peter ten Dijke

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

FAS-associated factor 1 (FAF1) antagonizes Wnt signaling by stimulating beta-catenin degradation. However, the molecular mechanism underlying this effect is unknown. Here, we demonstrate that the E3 ubiquitin ligase beta-transducin repeat-containing protein (beta-TrCP) is required for FAF1 to suppress Wnt signaling and that FAF1 specifically associates with the SCF (Skp1-Cul1-F-box protein)-beta-TrCP complex. Depletion of beta-TrCP reduced FAF1-mediated beta-catenin polyubiquitination and impaired FAF1 in antagonizing Wnt/beta-catenin signaling. FAF1 was shown to act as a scaffold for beta-catenin and beta-TrCP and thereby to potentiate beta-TrCP-mediated beta-catenin ubiquitination and degradation. Data mining revealed that FAF1 expression is statistically down-regulated in human breast carcinoma compared with normal breast tissue. Consistent with this, FAF1 expression is higher in epithelial-like MCF7 than mesenchymal-like MDA-MB-231 human breast cancer cells. Depletion of FAF1 in MCF7 cells resulted in increased beta-catenin accumulation and signaling. Importantly, FAF1 knockdown promoted a decrease in epithelial E-cadherin and an increase in mesenchymal vimentin expression, indicative for an epithelial to mesenchymal transition. Moreover, ectopic FAF1 expression reduces breast cancer cell migration in vitro and invasion/metastasis in vivo. Thus, our studies strengthen a tumor-suppressive function for FAF1.

Original languageEnglish
Pages (from-to)30701-30710
Number of pages10
JournalJournal of Biological Chemistry
Volume287
Issue number36
DOIs
Publication statusPublished - 31 Aug 2012

Keywords

  • EPITHELIAL-MESENCHYMAL TRANSITION
  • INTRACELLULAR DOMAIN AICD
  • DUAL-KINASE MECHANISM
  • WNT SIGNALING PATHWAY
  • BREAST-CANCER CELLS
  • KAPPA-B
  • TRANSCRIPTIONAL ACTIVATION
  • MAMMARY DEVELOPMENT
  • MEDIATED APOPTOSIS
  • DUCTAL CARCINOMA

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