title: 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.affiliation: Department of Molecular Cell Biology and Center for Biomedical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.forename: Theo
authors.initials: T
authors.lastname: van Laar
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.forename: Hans
authors.initials: H
authors.lastname: van Dam
authors.forename: Peter
authors.initials: P
authors.lastname: Ten Dijke
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D015398:Signal Transduction; D054875:Ubiquitination; D051153:Wnt Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; C495267:CTNNB1 protein, mouse; D002352:Carrier Proteins; C097186:Faf1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D046988:Proteasome Endopeptidase Complex