• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) negatively regulates TGF-beta (transforming growth factor-beta) signalling by inducing ubiquitin-mediated degradation of Smad2 and TGF-beta type I receptor.

Inhibitory Smad, Smad7, is a potent inhibitor of TGF-beta (transforming growth factor-beta) superfamily signalling. By binding to activated type I receptors, it prevents the activation of R-Smads (receptor-regulated Smads). To identify new components of the Smad pathway, we performed yeast two-hybrid screening using Smad7 as bait, and identified NEDD4-2 (neural precursor cell expressed, developmentally down-regulated 4-2) as a direct binding partner of Smad7. NEDD4-2 is structurally similar to Smurfs (Smad ubiquitin regulatory factors) 1 and 2, which were identified previously as E3 ubiquitin ligases for R-Smads and TGF-beta superfamily receptors. NEDD4-2 functions like Smurfs 1 and 2 in that it associates with TGF-beta type I receptor via Smad7, and induces its ubiquitin-dependent degradation. Moreover, NEDD4-2 bound to TGF-beta-specific R-Smads, Smads 2 and 3, in a ligand-dependent manner, and induced degradation of Smad2, but not Smad3. However, in contrast with Smurf2, NEDD4-2 failed to induce ubiquitination of SnoN (Ski-related novel protein N), although NEDD4-2 bound to SnoN via Smad2 more strongly than Smurf2. We showed further that overexpressed NEDD4-2 prevents transcriptional activity induced by TGF-beta and BMP, whereas silencing of the NEDD4-2 gene by siRNA (small interfering RNA) resulted in enhancement of the responsiveness to TGF-beta superfamily cytokines. These data suggest that NEDD4-2 is a member of the Smurf-like C2-WW-HECT (WW is Trp-Trp and HECT is homologous to the E6-accessory protein) type E3 ubiquitin ligases, which negatively regulate TGF-beta superfamily signalling through similar, but not identical, mechanisms to those used by Smurfs.

Pubmed ID: 15496141


  • Kuratomi G
  • Komuro A
  • Goto K
  • Shinozaki M
  • Miyazawa K
  • Miyazono K
  • Imamura T


The Biochemical journal

Publication Data

March 15, 2005

Associated Grants


Mesh Terms

  • Activin Receptors, Type I
  • Animals
  • Bone Morphogenetic Proteins
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus
  • Cytoplasm
  • DNA-Binding Proteins
  • Endosomal Sorting Complexes Required for Transport
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Mice
  • Protein Binding
  • Protein Transport
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • Signal Transduction
  • Smad2 Protein
  • Smad3 Protein
  • Smad6 Protein
  • Smad7 Protein
  • Trans-Activators
  • Transcription, Genetic
  • Transforming Growth Factor beta
  • Two-Hybrid System Techniques
  • Ubiquitin
  • Ubiquitin-Protein Ligases