轉化生長因子-β的1型受體（transforming growth factor-β type I receptor ，TβRI）在細胞膜上的定位及穩定性決定了細胞中TGF-β信號通路的水平。SMAD7–SMURF2複合體能夠靶向TβRI，並通過泛素化途徑將其降解。
本文研究者通過全基因組功能篩選發現，泛素特異蛋白酶4（ubiquitin-specific protease ，USP4）能夠增強TGF-β信號通路的水平。USP4能夠直接與TβRI相互作用，並阻止其泛素化降解途徑，從而使細胞質膜表面的TβRI維持在一個較高的水平。去除USP4可以減弱由TGF-β通路介導的上皮細胞向間充質細胞轉變的過程。
值得注意的是，與乳腺癌的不良預後有關的AKT蛋白（即蛋白激酶B）能夠直接與USP4作用並將其磷酸化，磷酸化的USP4能夠重新定位，從細胞核轉移到胞質和膜上，這對於維持USP4穩定性十分重要。研究人員還發現，去除USP4和抑制TβRI激酶能夠抑制AKT介導的乳腺癌細胞遷移。
這一研究揭示了USP4是TGF-β通路與AKT通路進行串話的決定性因子，並為防治AKT介導的乳腺癌細胞轉移提供了新思路。（生物谷 Bioon.com ）
USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor
Long Zhang,1, 6 FangFang Zhou,1, 6 Yvette Drabsch,1 Rui Gao,2 B. Ewa Snaar-Jagalska,3 Craig Mickanin,4 Huizhe Huang,5 Kelly-Ann Sheppard,4 Jeff A. Porter,4 Chris X. Lu4 & Peter ten Dijke1
The stability and membrane localization of the transforming growth factor-β (TGF-β) type I receptor (TβRI) determines the levels of TGF-β signalling. TβRI is targeted for ubiquitylation-mediated degradation by the SMAD7–SMURF2 complex. Here we performed a genome-wide gain-of-function screen and identified ubiquitin-specific protease (USP) 4 as a strong inducer of TGF-β signalling. USP4 was found to directly interact with TβRI and act as a deubiquitylating enzyme, thereby controlling TβRI levels at the plasma membrane. Depletion of USP4 mitigates TGF-β-induced epithelial to mesenchymal transition and metastasis. Importantly, AKT (also known as protein kinase B), which has been associated with poor prognosis in breast cancer, directly associates with and phosphorylates USP4. AKT-mediated phosphorylation relocates nuclear USP4 to the cytoplasm and membrane and is required for maintaining its protein stability. Moreover, AKT-induced breast cancer cell migration was inhibited by USP4 depletion and TβRI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-β and AKT signalling pathways.