Fei C, Li Z, Li C, Chen Y, Chen Z, He X, Mao L, Wang X, Zeng R, Li L

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 ...

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for non-proteolytic ubiquitination. Our data unambiguously demonstrate that Smurf1 ubiquitinates Axin through Lys (K) 29-linked poly-ubiquitin 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 KO MEFs. Next, we identified K789 and K821 in Axin as the ubiquitination sites by Smurf1. Consistently, Smurf1 could neither disrupt the interaction of 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 Wnt/β-catenin signaling pathway via modulating the activity of Axin.

Date: Aug. 19, 2013

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