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

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.