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Transforming growth factor  (TGF) is a multifunctional cytokine with potent regulatory effects on cell fate during embryogenesis, in the normal adult organism, and in cancer cells. In normal cells, the signal from the TGF ligand is transduced from the extracellular space to the cell nucleus by transmembrane serine-threonine kinase receptors in a highly specific manner. The dimeric ligand binding to the TGF Type II receptor (TRII) initiates the signal, and then recruits the TGF Type I receptor (TRI) into the complex, which activates TRI. This causes phosphorylation of receptor-activated Smad proteins Smad2 and Smad3 and promotes their nuclear translocation and transcriptional activity in complex with context-dependent transcription factors. In several of our most common forms of cancer, this pathway is instead regulated by polyubiquitination of TRI by the E3 ubiquitin ligase TRAF6, which is associated with TRI. The activation of TRAF6 promotes the proteolytic cleavage of TRI, liberating its intracellular domain (TRI-ICD). TRI-ICD enters the cancer cell nucleus in a manner dependent on the endosomal adaptor proteins APPL1/APPL2. Nuclear TRI-ICD promotes invasion by cancer cells and is recognized as acting distinctly and differently from the canonical TGF-Smad signaling pathway occurring in normal cells.

Lys63-Linked Polyubiquitination of Transforming Growth Factor β Type I Receptor (TβRI) Specifies Oncogenic Signaling