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. 2022 Feb 10;13(2):139. doi: 10.1038/s41419-022-04566-6

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© The Author(s) 2022

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 3 — TGF-β ligands bind to the TGF-β receptors and activate the SMADs proteins. USPs including USP4, USP11, USP15, USP26 and CYLD are associated with TGF-β signalling. Upon AKT-mediated phosphorylation, phosphorylated USP4 recruits to the activated TGF-β type I receptor directly and reverses receptor ubiquitination, leading to TGF-β signalling. USP11 deubiquitinates and stabilizes TGF-β type II receptor to promote TGF-β signalling. Reversed the polyubiquitination by SMAD specific E3 ubiquitin protein ligase 2 (Smurf2) and SMAD7, USP15 is recruited to the TGF-β type I receptor with scaffold protein SMAD7 as well and suppresses polyubiquitination and degradation of the receptor, positively regulating TGF-β signalling. USP26 is recognized as a negative regulator that deubiquitinates SMAD7 and stabilizes the interaction of SMAD7 and Smurf2, negatively regulating TGF-β signalling. CYLD decreases SMAD3 protein stability via an Akt-glycogen synthase kinase3β-hsc70-interacting protein-dependent manner, suppressing the activation of TGF-β signalling. CYLD also deubiquitinate Lys63-linked polyubiquitin chains of SMAD7 to regulate the activation of SMAD7-TAK1-TAB2/3 complex and transcription factor activator protein 1.