Abstract
Transforming growth factor-β (TGF-β) signaling is tightly regulated at the level of post-translational modification to transmit quantitative difference in ligand concentration into proportional transcriptional output. Ubiquitination is one such modification with several E3 ubiquitin ligases implicated in TGF-β signaling in marking crucial pathway components for proteasomal degradation. However, ubiquitination, particularly in the mono- or oligo-ubiquitin modifying form, is also known to regulate incorporation of substrate proteins into signaling complexes that involved in DNA repair, kinase activation, and endocytosis. This review focuses on recent advances in understanding the role of such non-degradative ubiquitination in TGF-β signaling.
Highlights
The transforming growth factor-b (TGF-b) superfamily consists of more than 30 secreted polypeptide growth factors including, but not limited to, TGF-bs, bone morphogenetic proteins (BMPs), activin/inhibin, growth and differentiation factors (GDFs) and nodal [1,2,3]
By carefully examining the levels of various pathway components and transcriptional readouts in mouse embryonic fibroblasts (MEFs) isolated from wild type, Smurf2-/, and Smurf1-/mice, we found that Smurf2 is a specific E3 ligase responsible for multiple mono-ubiquitination of Smad3 [22]
Concluding remark and perspective In contrast to an abrupt “turning-off” role of the degradative ubiquitination, the non-degradative ubiquitination exerts versatile regulation of TGF-b signaling through various mechanisms
Summary
The transforming growth factor-b (TGF-b) superfamily consists of more than 30 secreted polypeptide growth factors including, but not limited to, TGF-bs, bone morphogenetic proteins (BMPs), activin/inhibin, growth and differentiation factors (GDFs) and nodal [1,2,3]. Both Smurf1 and Smurf2 were initially identified as E3 ligases that modulate TGF-b and BMP signaling, subsequent studies expanded the repertoire of their substrates to many other signaling pathways, and even in the process of epithelial to mesenchymal transition where TGF-b signaling is intimately involved, Smurf1 was found in a complex with Par6 to promote the localized degradation of RhoA at cell junction rather than acting through controlling the levels of Smads or TbRI [23].
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