Negative regulation of transforming growth factor-beta (TGF-beta) signaling by WW domain-containing protein 1 (WWP1)

Oncogene. 2004 Sep 9;23(41):6914-23. doi: 10.1038/sj.onc.1207885.

Abstract

Smad7 negatively regulates transforming growth factor (TGF)-beta superfamily signaling by binding to activated type I receptors, thereby preventing the phosphorylation of receptor-regulated Smads (R-Smads), as well as by recruiting HECT-type E3 ubiquitin ligases to degrade type I receptors through a ubiquitin-dependent mechanism. To elucidate the regulatory mechanisms of TGF-beta signaling, we searched for novel members of proteins that interact with Smad7 using a yeast two-hybrid system. One of the proteins identified was the WW domain-containing protein 1 (WWP1) that is structurally related to Smad ubiquitin regulatory factors (Smurfs), E3 ubiquitin ligases for Smads and TGF-beta superfamily receptors. Using a TGF-beta-responsive reporter in mammalian cells, we found that WWP1 inhibited transcriptional activities induced by TGF-beta. Similar to Smurfs, WWP1 associated with Smad7 and induced its nuclear export, and enhanced binding of Smad7 to TGF-beta type I receptor to cause ubiquitination and degradation of the receptor. Consistent with these results, WWP1 inhibited phosphorylation of Smad2 induced by TGF-beta. WWP1 thus negatively regulates TGF-beta signaling in cooperation with Smad7. However, unlike Smurfs, WWP1 failed to ubiquitinate R-Smads and SnoN. Importantly, WWP1 and Smurfs were expressed in distinct patterns in human tissues and carcinoma cell lines, suggesting unique pathophysiological roles of WWP1 and Smurfs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Active Transport, Cell Nucleus
  • Activin Receptors, Type I / physiology
  • Animals
  • Cell Line
  • DNA-Binding Proteins / metabolism
  • DNA-Binding Proteins / physiology*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins / physiology
  • RNA, Messenger / analysis
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / physiology
  • Signal Transduction / physiology*
  • Smad2 Protein
  • Smad7 Protein
  • Trans-Activators / metabolism
  • Trans-Activators / physiology*
  • Transforming Growth Factor beta / pharmacology*
  • Two-Hybrid System Techniques
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / physiology*

Substances

  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Receptors, Transforming Growth Factor beta
  • SKIL protein, human
  • SMAD2 protein, human
  • SMAD7 protein, human
  • Smad2 Protein
  • Smad7 Protein
  • Trans-Activators
  • Transforming Growth Factor beta
  • Ubiquitin
  • SMURF2 protein, human
  • WWP1 protein, human
  • Ubiquitin-Protein Ligases
  • Protein-Serine-Threonine Kinases
  • Activin Receptors, Type I
  • Receptor, Transforming Growth Factor-beta Type I