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.

Stem cells are the self-renewing progenitors of several body tissues and are classified according to their origin and their ability to differentiate. Current research focuses on the potential uses of stem cells in medicine and how they can provide effective treatment for a range of diseases. This approach has resulted in the field of medical practice called regenerative medicine. To attain the promises of regenerative medicine, it is necessary to fully understand the biology and properties of stem cells, achieve their successful differentiation into functional tissues, overcome the barriers related to immune responses after administration, and assess any oncogenic properties that limit their use. The availability of human stem cells not only raises hope for cell replacement therapies, but also provides a system for understanding the mechanisms of embryonic development and disease progression. Nevertheless, it raises ethical concerns that need to be addressed before the use of stem cells in clinical practice.

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