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

Nat Cell Biol. 2012 Jun 17;14(7):717-26. doi: 10.1038/ncb2522.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / enzymology*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Membrane / metabolism*
  • Cell Movement
  • Enzyme Stability
  • Epithelial-Mesenchymal Transition
  • Female
  • Gene Expression Regulation
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mice
  • Mice, Knockout
  • Mutation
  • Neoplasm Invasiveness
  • Oncogene Proteins / deficiency
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism*
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / antagonists & inhibitors
  • Receptors, Transforming Growth Factor beta / genetics
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Signal Transduction
  • Time Factors
  • Transfection
  • Transforming Growth Factor beta / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Proteases
  • Ubiquitination
  • Zebrafish / embryology

Substances

  • Oncogene Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins
  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta
  • USP4 protein, human
  • Usp4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Receptor, Transforming Growth Factor-beta Type I
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases