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

Yabing Mu, Reshma Sundar, Noopur Thakur, Maria Ekman, Shyam Kumar Gudey, Mariya Yakymovych, Annika Hermansson, Helen Dimitriou, Maria Teresa Bengoechea-Alonso, Johan Ericsson, Carl-Henrik Heldin and Marene Landström ()
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Yabing Mu: Rudbeck Laboratory, Genetics and Pathology
Reshma Sundar: Rudbeck Laboratory, Genetics and Pathology
Noopur Thakur: Rudbeck Laboratory, Genetics and Pathology
Maria Ekman: Ludwig Institute for Cancer Research, Uppsala University
Shyam Kumar Gudey: Rudbeck Laboratory, Genetics and Pathology
Mariya Yakymovych: Ludwig Institute for Cancer Research, Uppsala University
Annika Hermansson: Rudbeck Laboratory, Genetics and Pathology
Helen Dimitriou: Rudbeck Laboratory, Genetics and Pathology
Maria Teresa Bengoechea-Alonso: Ludwig Institute for Cancer Research, Uppsala University
Johan Ericsson: Ludwig Institute for Cancer Research, Uppsala University
Carl-Henrik Heldin: Ludwig Institute for Cancer Research, Uppsala University
Marene Landström: Rudbeck Laboratory, Genetics and Pathology

Nature Communications, 2011, vol. 2, issue 1, 1-11

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1332

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