TRAF6 ubiquitinates TGF beta type I receptor to promote its cleavage and nuclear translocation in cancer
2011 (English)In: Nature Communications, ISSN 2041-1723, Vol. 2, no 330, 11- p.Article in journal (Refereed) Published
Transforming growth factor beta (TGF beta) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGF beta binding to type II and type I serine/threonine kinase receptors (T beta RII and T beta RI) causes activation of different intracellular signaling pathways. T beta RI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGF beta, via TRAF6, causes Lys63-linked polyubiquitination of T beta RI, promoting cleavage of T beta RI by TNF-alpha converting enzyme (TACE), in a PKC zeta-dependent manner. The liberated intracellular domain (ICD) of T beta RI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGF beta-induced invasion of cancer cells is TACE- and PKC zeta-dependent and the T beta RI ICD is localized in the nuclei of different kinds of tumour cells in tissue sections. Thus, our data reveal a specific role for T beta RI in TGF beta mediated tumour invasion.
Place, publisher, year, edition, pages
London: Nature Publishing Group , 2011. Vol. 2, no 330, 11- p.
Cancer and Oncology
IdentifiersURN: urn:nbn:se:umu:diva-47676DOI: 10.1038/ncomms1332ISI: 000294802600035OAI: oai:DiVA.org:umu-47676DiVA: diva2:445115