USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-β type I receptor

被引：272

作者：

Zhang, Long ^{[1
]}

Zhou, FangFang ^{[1
]}

Drabsch, Yvette ^{[1
]}

Gao, Rui ^{[2
]}

Snaar-Jagalska, B. Ewa ^{[3
]}

Mickanin, Craig ^{[4
]}

Huang, Huizhe ^{[5
]}

Sheppard, Kelly-Ann ^{[4
]}

Porter, Jeff A. ^{[4
]}

Lu, Chris X. ^{[4
]}

ten Dijke, Peter ^{[1
]}

机构：

[1] Leiden Univ, Med Ctr, Dept Mol Cell Biol, NL-2300 RC Leiden, Netherlands

[2] Xiamen Univ Ctr, Sch Life Sci, Xiamen 361005, Fujian, Peoples R China

[3] Leiden Univ, Inst Biol, NL-2333 CC Leiden, Netherlands

[4] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[5] Chonqing Med Univ, Fac Basic Med Sci, Chongqing 400016, Peoples R China

来源：

NATURE CELL BIOLOGY | 2012年 / 14卷 / 07期

关键词：

MESENCHYMAL TRANSITION; DEPENDENT DEGRADATION; UBIQUITIN LIGASE; TARGETS; GROWTH; INHIBITION; SMURF2; TRANSCRIPTION; METASTASIS; ACTIVATION;

D O I：

10.1038/ncb2522

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The stability and membrane localization of the transforming growth factor-beta (TGF-beta) type I receptor (T beta RI) determines the levels of TGF-beta signalling. T beta RI 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-beta signalling. USP4 was found to directly interact with T beta RI and act as a deubiquitylating enzyme, thereby controlling T beta RI levels at the plasma membrane. Depletion of USP4 mitigates TGF-beta-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 T beta RI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT signalling pathways.

引用

页码：717 / 726

页数：10

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