title: Smurf1-mediated Lys29-linked nonproteolytic polyubiquitination of axin negatively regulates Wnt/β-catenin signaling.
abstract: Ubiquitination plays important and diverse roles in modulating protein functions. As a C2-WW-HECT-type ubiquitin ligase, Smad ubiquitination regulatory factor 1 (Smurf1) commonly serves to regulate ubiquitin-dependent protein degradation in a number of signaling pathways. Here, we report a novel function of Smurf1 in regulating Wnt/β-catenin signaling through targeting axin for nonproteolytic ubiquitination. Our data unambiguously demonstrate that Smurf1 ubiquitinates axin through Lys 29 (K29)-linked polyubiquitin chains. Unexpectedly, Smurf1-mediated axin ubiquitination does not lead to its degradation but instead disrupts its interaction with the Wnt coreceptors LRP5/6, which subsequently attenuates Wnt-stimulated LRP6 phosphorylation and represses Wnt/β-catenin signaling. The inhibitory function of Smurf1 on Wnt/β-catenin signaling is further evidenced by analysis with Smurf1 knockout murine embryonic fibroblasts. We next identified K789 and K821 in axin as the ubiquitination sites by Smurf1. Consistently, Smurf1 could neither disrupt the interaction of an axin(K789/821R) double mutant with LRP5/6 nor attenuate the phosphorylation of LRP6 in axin(K789/821R)-expressing cells. Collectively, our studies uncover Smurf1 as a new regulator for the Wnt/β-catenin signaling pathway via modulating the activity of axin.
authors: State Key Laboratory of Molecular Biology.
authors: Cong
authors: C
authors: Fei
authors: Zhenfei
authors: Z
authors: Li
authors: Chen
authors: C
authors: Li
authors: Yuelei
authors: Y
authors: Chen
authors: Zhangcheng
authors: Z
authors: Chen
authors: Xiaoli
authors: X
authors: He
authors: Li
authors: L
authors: Mao
authors: Xin
authors: X
authors: Wang
authors: Rong
authors: R
authors: Zeng
authors: Lin
authors: L
authors: Li
mesh_terms: D000818:Animals; D060466:Axin Protein / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D010766:Phosphorylation; D015398:Signal Transduction; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D060466:Axin Protein; C555452:Axin1 protein, mouse; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; D025801:Ubiquitin; D051153:Wnt Proteins; D051176:beta Catenin; C492381:Smurf1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D008239:Lysine
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