Fas-associated factor 1 antagonizes Wnt signaling by promoting β-catenin degradation.

Abstract	The canonical Wnt pathway plays an important role in the regulation of cell proliferation and differentiation. Activation of this signaling pathway causes disruption of the Axin/adenomatous polyposis coli/glycogen synthase kinase 3β complex, resulting in stabilization of β-catenin and its association with lymphoid enhancer factor/T-cell factor in the nucleus. Here, we identify Fas-associated factor 1 (FAF1) as a negative regulator of Wnt/β-catenin signaling. We found overexpression of FAF1 to strongly inhibit Wnt-induced transcriptional reporter activity and to counteract Wnt-induced β-catenin accumulation. Moreover, knockdown of FAF1 resulted in an increase in β-catenin levels and in activation of Wnt/β-catenin-induced transcription. FAF1 was found to interact with β-catenin upon inhibition of proteasome. Ectopic expression of FAF1 promoted β-catenin degradation by enhancing its polyubiquitination. Functional studies in C2C12 myoblasts and KS483 preosteoblastic cells showed that FAF1 depletion resulted in activation of endogenous Wnt-induced genes and enhanced osteoblast differentiation, whereas FAF1 overexpression had the opposite effect. These results identify FAF1 as a novel inhibitory factor of canonical Wnt signaling pathway.
Authors	Long Zhang, Fangfang Zhou, Theo van Laar, Juan Zhang, Hans van Dam, Peter Ten Dijke
Journal	Molecular biology of the cell (Mol Biol Cell) Vol. 22 Issue 9 Pg. 1617-24 (May 2011) ISSN: 1939-4586 [Electronic] United States
PMID	21411632 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Adaptor Proteins, Signal Transducing Apoptosis Regulatory Proteins CTNNB1 protein, mouse Carrier Proteins Faf1 protein, mouse Intracellular Signaling Peptides and Proteins Wnt Proteins beta Catenin Proteasome Endopeptidase Complex
Topics	Adaptor Proteins, Signal Transducing Animals Apoptosis Regulatory Proteins Carrier Proteins (genetics, metabolism) Cell Differentiation Cell Line Cell Proliferation Gene Knockdown Techniques Humans Immunoblotting Immunoprecipitation Intracellular Signaling Peptides and Proteins Mice Polymerase Chain Reaction Proteasome Endopeptidase Complex (metabolism) Signal Transduction Ubiquitination Wnt Proteins (antagonists & inhibitors, genetics, metabolism) beta Catenin (analysis, genetics, metabolism)

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