Ubiquitin ligase Nedd4L targets activated Smad2/3 to limit TGF-beta signaling.

Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
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.
Mesh Terms:
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
Mol. Cell Nov. 13, 2009; 36(3);457-68 [PUBMED:19917253]
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