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USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGFbeta type I receptor

Zhang, Long, Zhou, Fangfang, Mickanin, Craig, Sheppard, Kelly-Ann, Porter, Jeffrey, Lu, Chris and ten Dijke, Peter (2012) USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGFbeta type I receptor. Nature Cell Biology, 14 (7). pp. 717-726. ISSN 1465-7392


The stability and membrane localization of the transforming growth factor-beta (TGF-beta) type I receptor (TbetaRI) determines the levels of TGF-beta signalling. TbetaRI is targeted for ubiquitylation-mediated degradation by the SMAD7SMURF2 complex. Here we performed
a genome-wide gain-of-function screen and identied ubiquitin-specic protease (USP) 4 as a strong inducer of TGF-beta signalling.
USP4 was found to directly interact with TRI and act as a deubiquitylating enzyme, thereby controlling TbetaRI 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 TRI
kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT
signalling pathways.

Item Type: Article
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Additional Information: This journal is not in the list for the paid open access option. Can archive pre-print (ie pre-refereeing).
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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