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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

Authors

  • Gao S
  • Alarc√≥n C
  • Sapkota G
  • Rahman S
  • Chen PY
  • Goerner N
  • Macias MJ
  • Erdjument-Bromage H
  • Tempst P
  • Massagu√© J

Journal

Molecular cell

Publication Data

November 13, 2009

Associated Grants

  • Agency: PHS HHS, Id: BFU2005-06276
  • Agency: PHS HHS, Id: BFU2008-02795
  • Agency: NCI NIH HHS, Id: CA08748
  • Agency: NCI NIH HHS, Id: CA34610
  • Agency: NCI NIH HHS, Id: R37 CA034610
  • Agency: NCI NIH HHS, Id: R37 CA034610-27
  • Agency: Howard Hughes Medical Institute, Id:

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