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

Transforming growth factor β (TGFβ) 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 TGFβ 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 TGFβ Type II receptor (TβRII) initiates the signal and then recruits the TGFβ Type I receptor (TβRI) into the complex, which activates TβRI. 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 TβRI by the E3 ubiquitin ligase TRAF6, which is associated with TβRI. The activation of TRAF6 promotes the proteolytic cleavage of TβRI, liberating its intracellular domain (TβRI-ICD). TβRI-ICD enters the cancer cell nucleus in a manner dependent on the endosomal adaptor proteins APPL1/APPL2. Nuclear TβRI-ICD promotes invasion by cancer cells and is recognized as acting distinctly and differently from the canonical TGFβ-Smad signaling pathway occurring in normal cells.