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

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.

Up‐regulated deubiquitinase USP4 plays an oncogenic role in melanoma

“…Specifically, up‐regulated USP4 potentiated the growth and invasion of colorectal cancer though deubiquitination and stabilization of PRL‐3 19. In addition, USP4 transduced Akt activation to TGF‐β signalling by deubiquitinating and stabilizing TGF‐β type I receptor, thus augmented breast cancer cell invasion and migration 33. These studies demonstrate USP4 as a powerful tumour promoter and an important determinant for canonical oncogenic signalling.…”

“…USP4 has been greatly implicated in regulating tumour metastasis in breast cancer, lung cancer and colorectal cancer 19, 33, 35, 36. Notably, the loss of E‐cadherin expression accounted for USP4‐mediated augmentation of tumour metastatic capacity in all of these cancers.…”

“…Importantly, Wnt signalling and TGF‐β signalling are 2 critical pro‐metastatic signalling pathways in various cancers with the positively regulatory impact on EMT, including melanoma 37. Several lines of evidence have revealed that USP4 was tightly associated with these 2 canonical pathways 33, 36, 38. Specifically, USP4 could directly interact with TGF‐β type I receptor (TRI) and stabilize TRI levels at the plasma membrane though its deubiquitinating activity, thereby maintaining the sustained activation of TGF‐β signalling 33.…”

Deubiquitylases From Genes to Organism

“…Differential phosphorylation of USP8 at S680 and dephosphorylation of USP37 during M-phase of the cell cycle correspond with enhanced and reduced activity, respectively (100,176,190). USP8 also undergoes translocation to endosomes following acute EGFR stimulation (219), whilst USP4 translocates from nucleus to cytoplasm following phosphorylation by Akt (290). These examples illustrate a further mechanism of regulation, by dynamically changing the palette of associates and substrates to colocalizing proteins.…”

“…The individual effects of these may be more or less pronounced depending on cellular context (2,6,61,272,290). USP15 has also been associated with many other cellular signaling events including the MAP kinase pathway (90), ␤-catenin stability (99), and the NF B pathway (232).…”