A Tale of Two Proteins: Differential Roles and Regulation of Smad2 and Smad3 in TGF-beta Signaling

J Cell Biochem. 2007 May 1;101(1):9-33. doi: 10.1002/jcb.21255.

Abstract

Transforming growth factor-beta (TGF-beta) is an important growth inhibitor of epithelial cells, and insensitivity to this cytokine results in uncontrolled cell proliferation and can contribute to tumorigenesis. Smad2 and Smad3 are direct mediators of TGF-beta signaling, however little is known about the selective activation of Smad2 versus Smad3. The Smad2 and Smad3 knockout mouse phenotypes and studies comparing Smad2 and Smad3 activation of TGF-beta target genes, suggest that Smad2 and Smad3 have distinct roles in TGF-beta signaling. The observation that TGF-beta inhibits proliferation of Smad3-null mammary gland epithelial cells, whereas Smad3 deficient fibroblasts are only partially growth inhibited, suggests that Smad3 has a different role in epithelial cells and fibroblasts. Herein, the current understanding of Smad2 and Smad3-mediated TGF-beta signaling and their relative roles are discussed, in addition to potential mechanisms for the selective activation of Smad2 versus Smad3. Since alterations in the TGF-beta signaling pathway play an important role in promoting tumorigenesis and cancer progression, methods for therapeutic targeting of the TGF-beta signaling pathway are being pursued. Determining how Smad2 or Smad3 differentially regulate the TGF-beta response may translate into developing more effective strategies for cancer therapy.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Gene Expression Regulation*
  • Mice
  • Mice, Knockout
  • Models, Biological
  • Signal Transduction*
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism*
  • Smad3 Protein / genetics
  • Smad3 Protein / metabolism*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Transforming Growth Factor beta / metabolism*

Substances

  • Smad2 Protein
  • Smad3 Protein
  • Transcription Factors
  • Transforming Growth Factor beta