title: TRAF6 ubiquitinates TGFβ type I receptor to promote its cleavage and nuclear translocation in cancer.
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.
authors.affiliation: Rudbeck Laboratory, Department of Immunology, Genetics and Pathology, SE-751 85 Uppsala, Sweden.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Mu
authors.forename: Reshma
authors.initials: R
authors.lastname: Sundar
authors.forename: Noopur
authors.initials: N
authors.lastname: Thakur
authors.forename: Maria
authors.initials: M
authors.lastname: Ekman
authors.forename: Shyam Kumar
authors.initials: SK
authors.lastname: Gudey
authors.forename: Mariya
authors.initials: M
authors.lastname: Yakymovych
authors.forename: Annika
authors.initials: A
authors.lastname: Hermansson
authors.forename: Helen
authors.initials: H
authors.lastname: Dimitriou
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Bengoechea-Alonso
authors.forename: Johan
authors.initials: J
authors.lastname: Ericsson
authors.forename: Carl-Henrik
authors.initials: CH
authors.lastname: Heldin
authors.forename: Marene
authors.initials: M
authors.lastname: Landström
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism / Q000502:physiology; D000072198:ADAM17 Protein; D021581:Active Transport, Cell Nucleus; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009361:Neoplasm Invasiveness; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D048029:TNF Receptor-Associated Factor 6 / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism / Q000502:physiology; D054875:Ubiquitination
chemical_list: D007527:Isoenzymes; D018125:Receptors, Transforming Growth Factor beta; D000071250:Snail Family Transcription Factors; D048029:TNF Receptor-Associated Factor 6; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D011493:Protein Kinase C; D051722:ADAM Proteins; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse