Zhang L, Zhou F, Li Y, Drabsch Y, Zhang J, van Dam H, Ten Dijke P

FAS-associated factor 1 (FAF1) antagonizes Wnt signaling by stimulating β-catenin degradation. However, the molecular mechanism underlying this effect is unknown. Here, we demonstrate that the E3 ubiquitin ligase β-TrCP is required for FAF1 to suppress Wnt signaling and that FAF1 specifically associates with the SCF ( Skp1/Cul1/F-box protein)/β-TrCP complex. Depletion ...

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of β-TrCP reduced FAF1-mediated β-catenin polyubiquitination and impaired FAF1 in antagonizing Wnt/β-catenin signaling. FAF1 was shown to act as a scaffold for β-catenin and β-TrCP and thereby to potentiate β-TrCP mediated β-catenin ubiquitination and degradation. Data mining revealed that FAF1 expression is statistically downregulated in human breast carcinoma when compared to 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 β-catenin accumulation and signaling. Importantly, FAF1 knock down 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.

Date: Jun. 22, 2012

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