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
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / metabolism
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ADAM Proteins / physiology
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ADAM17 Protein
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Active Transport, Cell Nucleus
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Animals
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Cells, Cultured
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E1A-Associated p300 Protein / metabolism
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Humans
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Isoenzymes / metabolism
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Isoenzymes / physiology
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Matrix Metalloproteinase 2 / metabolism
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Mice
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Neoplasm Invasiveness*
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Protein Kinase C / metabolism
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Protein Kinase C / physiology
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Protein Structure, Tertiary
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Receptors, Transforming Growth Factor beta / chemistry
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Receptors, Transforming Growth Factor beta / metabolism*
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Snail Family Transcription Factors
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TNF Receptor-Associated Factor 6 / physiology*
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Transcription Factors / metabolism
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Transforming Growth Factor beta / metabolism
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Transforming Growth Factor beta / physiology
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Ubiquitination
Substances
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Isoenzymes
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Receptors, Transforming Growth Factor beta
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Snail Family Transcription Factors
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TNF Receptor-Associated Factor 6
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Transcription Factors
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Transforming Growth Factor beta
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E1A-Associated p300 Protein
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EP300 protein, human
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Protein Kinase C
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ADAM Proteins
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MMP2 protein, human
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Matrix Metalloproteinase 2
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ADAM17 Protein
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ADAM17 protein, human
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Adam17 protein, mouse