Ubiquitin Ligase Nedd4L Targets Activated Smad2/3 to Limit TGF-β Signaling
Copyright policy )Ubiquitin Ligase Nedd4L Targets Activated Smad2/3 to Limit TGF-β Signaling
TGF-beta induces phosphorylation of the transcription factors Smad2 and Smad3 at the C terminus as well as at an interdomain linker region. TGF-beta-induced linker phosphorylation marks the activated Smad proteins for proteasome-mediated destruction. Here, we identify Nedd4L as the ubiquitin ligase responsible for this step. Through its WW domain, Nedd4L specifically recognizes a TGF-beta-induced phosphoThr-ProTyr motif in the linker region, resulting in Smad2/3 polyubiquitination and degradation. Nedd4L is not interchangeable with Smurf1, a ubiquitin ligase that targets BMP-activated, linker-phosphorylated Smad1. Nedd4L limits the half-life of TGF-beta-activated Smads and restricts the amplitude and duration of TGF-beta gene responses, and in mouse embryonic stem cells, it limits the induction of mesoendodermal fates by Smad2/3-activating factors. Hierarchical regulation is provided by SGK1, which phosphorylates Nedd4L to prevent binding of Smad2/3. Previously identified as a regulator of renal sodium channels, Nedd4L is shown here to play a broader role as a general modulator of Smad turnover during TGF-beta signal transduction.
- University of Dundee United Kingdom
- Barcelona Institute for Science and Technology Spain
- Howard Hughes Medical Institute United States
- Institució dels Centres de Recerca de Catalunya Spain
- Memorial Sloan Kettering Cancer Center United States
570, Nedd4 Ubiquitin Protein Ligases, Immunoblotting, Molecular Sequence Data, Protein Serine-Threonine Kinases, Cell Line, Immediate-Early Proteins, Mice, Animals, Humans, Amino Acid Sequence, Phosphorylation, Polyubiquitin, Molecular Biology, Cells, Cultured, Embryonic Stem Cells, Endosomal Sorting Complexes Required for Transport, Sequence Homology, Amino Acid, 500, Cell Biology, RNA Interference, HeLa Cells, Protein Binding, Signal Transduction
570, Nedd4 Ubiquitin Protein Ligases, Immunoblotting, Molecular Sequence Data, Protein Serine-Threonine Kinases, Cell Line, Immediate-Early Proteins, Mice, Animals, Humans, Amino Acid Sequence, Phosphorylation, Polyubiquitin, Molecular Biology, Cells, Cultured, Embryonic Stem Cells, Endosomal Sorting Complexes Required for Transport, Sequence Homology, Amino Acid, 500, Cell Biology, RNA Interference, HeLa Cells, Protein Binding, Signal Transduction
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