Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta 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.
Pubmed ID: 19917253 RIS Download
Amino Acid Sequence | Animals | Cell Line | Cells, Cultured | Embryonic Stem Cells | Endosomal Sorting Complexes Required for Transport | HeLa Cells | Humans | Immediate-Early Proteins | Immunoblotting | Mice | Molecular Sequence Data | Phosphorylation | Polyubiquitin | Protein Binding | Protein-Serine-Threonine Kinases | RNA Interference | Sequence Homology, Amino Acid | Signal Transduction | Smad2 Protein | Smad3 Protein | Transforming Growth Factor beta | Ubiquitin-Protein Ligases