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, 14 (7), 717-26

USP4 Is Regulated by AKT Phosphorylation and Directly Deubiquitylates TGF-β Type I Receptor


USP4 Is Regulated by AKT Phosphorylation and Directly Deubiquitylates TGF-β Type I Receptor

Long Zhang et al. Nat Cell Biol.


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.

Comment in

  • Ubiquitin Removal in the TGF-β Pathway
    K Aggarwal et al. Nat Cell Biol 14 (7), 656-7. PMID 22743709.
    The transforming growth factor (TGF-β) pathway is regulated by ubiquitin-mediated proteolysis at different levels. Two studies now identify deubiquitinating enzymes (DUBs …

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