Regulated intramembrane proteolysis of the TGFβ type I receptor conveys oncogenic signals

Abstract

ABSTRACT: Cancer cells produce high levels of TGFβ, a multipotent cytokine. Binding of TGFβ to its cell surface receptors, the transmembrane serine/threonine kinases TβRII and TβRI, causes phosphorylation and activation of intracellular latent Smad transcription factors. Nuclear Smads act in concert with specific transcription factors to reprogram epithelial cells to become invasive mesenchymal cells. TGFβ also propagates non-canonical signals, so it is crucial to have a better understanding of the underlying molecular mechanisms which favor this pathway. Here we highlight our recent discovery that TGFβ promotes the proteolytic cleavage of TβRI in cancer cells, resulting in the liberation and nuclear translocation of its intracellular domain, acting as co-regulator to transcribe pro-invasive genes. This newly identified oncogenic TGFβ pathway resembles the Notch signaling pathway. We discuss our findings in relation to Notch and provide a short overview of other growth factors that transduce signals via nuclear translocation of their cell surface receptors.