TRAF6 ubiquitinates TGF? type I receptor to promote its cleavage and nuclear translocation in cancer.

ABSTRACT: Transforming growth factor ? (TGF?) is a pluripotent cytokine promoting epithelial cell plasticity during morphogenesis and tumour progression. TGF? binding to type II and type I serine/threonine kinase receptors (T?RII and T?RI) causes activation of different intracellular signaling pathways. T?RI is associated with the ubiquitin ligase tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6). Here we show that TGF?, via TRAF6, causes Lys63-linked polyubiquitination of T?RI, promoting cleavage of T?RI by TNF-alpha converting enzyme (TACE), in a PKC?-dependent manner. The liberated intracellular domain (ICD) of T?RI associates with the transcriptional regulator p300 to activate genes involved in tumour cell invasiveness, such as Snail and MMP2. Moreover, TGF?-induced invasion of cancer cells is TACE- and PKC?- dependent and the T?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?RI in TGF? mediated tumour invasion.

SUBMITTER: Mu Y 

PROVIDER: S-EPMC3113296 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature