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Nat.Cell.Bio:发现介导TGF-β 和AKT信号通路串话的重要因子

来源:生物谷 2012-06-24 23:09

转化生长因子-β的1型受体(transforming growth factor-β type I receptor ,TβRI)在细胞膜上的定位及稳定性决定了细胞中TGF-β信号通路的水平。SMAD7–SMURF2复合体能够靶向TβRI,并通过泛素化途径将其降解。

本文研究者通过全基因组功能筛选发现,泛素特异蛋白酶4(ubiquitin-specific protease ,USP4)能够增强TGF-β信号通路的水平。USP4能够直接与TβRI相互作用,并阻止其泛素化降解途径,从而使细胞质膜表面的TβRI维持在一个较高的水平。去除USP4可以减弱由TGF-β通路介导的上皮细胞向间充质细胞转变的过程。

值得注意的是,与乳腺癌的不良预后有关的AKT蛋白(即蛋白激酶B)能够直接与USP4作用并将其磷酸化,磷酸化的USP4能够重新定位,从细胞核转移到胞质和膜上,这对于维持USP4稳定性十分重要。研究人员还发现,去除USP4和抑制TβRI激酶能够抑制AKT介导的乳腺癌细胞迁移。

这一研究揭示了USP4是TGF-β通路与AKT通路进行串话的决定性因子,并为防治AKT介导的乳腺癌细胞转移提供了新思路。(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.

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