TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer

Nat Commun. 2011;2:330. doi: 10.1038/ncomms1332.

Abstract

Transforming growth factor β (TGFβ) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGFβ binding to type II and type I serine/threonine kinase receptors (TβRII and TβRI) causes activation of different intracellular signaling pathways. TβRI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGFβ, via TRAF6, causes Lys63-linked polyubiquitination of TβRI, promoting cleavage of TβRI by TNF-alpha converting enzyme (TACE), in a PKCζ-dependent manner. The liberated intracellular domain (ICD) of TβRI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGFβ-induced invasion of cancer cells is TACE- and PKCζ- dependent and the TβRI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for TβRI in TGFβ mediated tumour invasion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / metabolism
  • ADAM Proteins / physiology
  • ADAM17 Protein
  • Active Transport, Cell Nucleus
  • Animals
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • E1A-Associated p300 Protein / metabolism
  • Humans
  • Isoenzymes / metabolism
  • Isoenzymes / physiology
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Neoplasm Invasiveness*
  • Protein Kinase C / metabolism
  • Protein Kinase C / physiology
  • Protein Structure, Tertiary
  • Receptors, Transforming Growth Factor beta / chemistry
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Snail Family Transcription Factors
  • TNF Receptor-Associated Factor 6 / physiology*
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / physiology
  • Ubiquitination

Substances

  • Isoenzymes
  • Receptors, Transforming Growth Factor beta
  • Snail Family Transcription Factors
  • TNF Receptor-Associated Factor 6
  • Transcription Factors
  • Transforming Growth Factor beta
  • E1A-Associated p300 Protein
  • EP300 protein, human
  • Protein Kinase C
  • ADAM Proteins
  • MMP2 protein, human
  • Matrix Metalloproteinase 2
  • ADAM17 Protein
  • ADAM17 protein, human
  • Adam17 protein, mouse