Wang Y, Mao A, Liu J, Li P, Zheng S, Tong T, Li Z, Zhang H, Ma L, Lin J, Pang Z, Han Q, Qi F, Zhang X, Chen M, He X, Zhang X, Fei T, Liu BF, Gao D, Cao L, Wang Q, Li Y, Sheng R

Wnt/?-catenin signaling is a conserved pathway crucially governing development, homeostasis, and oncogenesis. Discoveries of its regulators hold great values in both basic and translational research. Through screening, we identified a deubiquitinase, USP10, as a critical modulator of ?-catenin. Mechanistically, USP10 binds to key scaffold Axin1 via conserved motifs and stabilizes ...

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Axin1 through K48-linked deubiquitination. Surprisingly, USP10 physically tethers Axin1 and ?-catenin and promotes the phase separation for ?-catenin suppression regardless of the enzymatic activity. Function-wise, USP10 enzymatic activity preferably regulates embryonic development and both the enzymatic activity and physical function jointly control intestinal homeostasis by antagonizing ?-catenin. In colorectal cancer, USP10 substantially represses cancer growth mainly through physical promotion of phase separation and correlates with Wnt/?-catenin magnitude clinically. Collectively, we discovered USP10 functioning in multiple biological processes against ?-catenin and unearthed the enzyme-dependent and -independent "dual-regulating" mechanism. These two functions of USP10 work in parallel and are context dependent.

Date: Nov. 16, 2023

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