Negative Regulation of TGF-β Signaling

概要

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TGF-βs (transforming growth factor-βs) are multifunctional peptides that regulate growth and differentiation of various types of cells. TGF-βs are known to potently induce tissue fibrosis in vivo. TGF-βs and related proteins bind to type II and type I serine/threonine kinase receptors, which mediate intracellular signals through Smad proteins. Of three subtypes of Smads, receptor-regulated Smads (R-Smads) are phosphorylated by the serine/threonine kinase receptors, form complexes with common-mediator Smad (Co-Smad), and translocate into the nucleus, where they act as components of transcription factor complexes. Inhibitory Smads (I-Smads) and transcriptional co-repressors, including c-Ski and SnoN, repress Smad signaling. Smad7 is an I-Smad which is induced by TGF-β, stably interacts with activated TGF-β type I receptor (TβR-I), and interferes with signaling by R-Smads. We have found that Smurfl, an E3 ubiquitin ligase for BMP-specific Smads, also interacts with Smad7 and induces Smad7-ubiquitination and its translocation into the cytoplasm. In addition, Smurfl associates with TβR-I through Smad7, with subsequent enhancement of turnover of TβR-I and Smad7. The N-terminal C2 domain of Smurfl plays an important role in targeting the Smurfl -Smad7 complex to the plasma membrane. These results reveal that Smad7 induces degradation of TβR-I through recruitment of an E3 ligase to the cell surface receptor.
日本結合組織学会の論文