Regulation of TGF-beta Family Signaling by E3 Ubiquitin Ligases

Cancer Sci. 2008 Nov;99(11):2107-12. doi: 10.1111/j.1349-7006.2008.00925.x. Epub 2008 Sep 18.


Members of the transforming growth factor-beta (TGF-beta) family, including TGF-beta, activin and bone morphogenetic proteins (BMPs), are multifunctional proteins that regulate a wide variety of cellular responses, such as proliferation, differentiation, migration and apoptosis. Alterations in their downstream signaling pathways are associated with a range of human diseases like cancer. TGF-beta family members transduce signals through membrane serine/threonine kinase receptors and intracellular Smad proteins. The ubiquitin-proteasome pathway, an evolutionarily conserved cascade, tightly regulates TGF-beta family signaling. In this pathway, E3 ubiquitin ligases play a crucial role in the recognition and degradation of target proteins by the 26S proteasomes. Smad degradation regulates TGF-beta family signaling; HECT (homologous to the E6-accessory protein C-terminus)-type E3 ubiquitin ligases, Smad ubiquitin regulatory factor 1 (Smurf1), Smurf2, and a RING-type E3 ubiquitin ligase, ROC1-SCF(Fbw1a) have been implicated in Smad degradation. Smurf1 and Smurf2 bind to TGF-beta family receptors via the inhibitory Smads, Smad6 and Smad7, to induce their ubiquitin-dependent degradation. Arkadia, a RING-type E3 ubiquitin ligase, induces the ubiquitination and degradation of Smad7 and corepressors, c-Ski and SnoN, to enhance TGF-beta family signaling. Abnormalities in E3 ubiquitin ligases that control components of TGF-beta family signaling may lead to the development and progression of various cancers.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Humans
  • Models, Biological
  • Nuclear Proteins / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Signal Transduction*
  • Transforming Growth Factor beta / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin-Protein Ligases / metabolism*


  • Nuclear Proteins
  • Transforming Growth Factor beta
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Proteasome Endopeptidase Complex