Abstract：
: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.
journal_name
Nat Cell Bioljournal_title
Nature cell biologyauthors
Zhang L,Zhou F,Drabsch Y,Gao R,Snaar-Jagalska BE,Mickanin C,Huang H,Sheppard KA,Porter JA,Lu CX,ten Dijke Pdoi
10.1038/ncb2522subject
Has Abstractpub_date
2012-06-17 00:00:00pages
717-26issue
7eissn
1465-7392issn
1476-4679pii
ncb2522journal_volume
14pub_type
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