| First Author | Zhang L | Year | 2012 |
| Journal | Nat Cell Biol | Volume | 14 |
| Issue | 7 | Pages | 717-26 |
| PubMed ID | 22706160 | Mgi Jnum | J:190463 |
| Mgi Id | MGI:5448892 | Doi | 10.1038/ncb2522 |
| Citation | Zhang L, et al. (2012) USP4 is regulated by AKT phosphorylation and directly deubiquitylates TGF-beta type I receptor. Nat Cell Biol 14(7):717-26 |
| abstractText | 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 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 TbetaRI 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 TbetaRI kinase inhibition. Our results uncover USP4 as an important determinant for crosstalk between TGF-beta and AKT signalling pathways. |
