Itch E3 Ligase-Mediated Regulation of TGF-β Signaling by Modulating Smad2 Phosphorylation
Copyright policy )Itch E3 Ligase-Mediated Regulation of TGF-β Signaling by Modulating Smad2 Phosphorylation
Protein ubiquitination has been implicated in the intracellular biochemical events transduced by TGF-beta receptor via different mechanisms including the degradation of Smads or their binding proteins. Here we show that loss of Itch E3 ligase in mouse embryonic fibroblasts (MEFs) results in reduced susceptibility of TGF-beta-induced cell growth arrest and decreased phosphorylation of Smad2, without apparent alteration in protein levels for Smad2, Smad4, and Smad7 in Itch-/- MEFs. Itch promotes ubiquitination of Smad2 and augments Smad2 phosphorylation that requires an intact ligase activity of Itch. Moreover, Itch facilitates complex formation between TGF-beta receptor and Smad2 and enhances TGF-beta-induced transcription. This study reveals a previously unrecognized positive TGF-beta signaling pathway via proteolysis-independent ubiquitination.
- La Jolla Institute For Allergy & Immunology United States
Male, Mice, Knockout, Transcription, Genetic, Ubiquitin, Ubiquitin-Protein Ligases, Cell Biology, Smad2 Protein, Fibroblasts, Up-Regulation, DNA-Binding Proteins, Mice, Fetus, Transforming Growth Factor beta, Trans-Activators, Animals, Female, Phosphorylation, Molecular Biology, Receptors, Transforming Growth Factor beta, Cell Division, Cells, Cultured, Signal Transduction
Male, Mice, Knockout, Transcription, Genetic, Ubiquitin, Ubiquitin-Protein Ligases, Cell Biology, Smad2 Protein, Fibroblasts, Up-Regulation, DNA-Binding Proteins, Mice, Fetus, Transforming Growth Factor beta, Trans-Activators, Animals, Female, Phosphorylation, Molecular Biology, Receptors, Transforming Growth Factor beta, Cell Division, Cells, Cultured, Signal Transduction
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