A tale of two proteins: differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling.

Brown KA, Pietenpol JA, Moses HL
J Cell Biochem. 2007 101 (1): 9-33

PMID: 17340614 · DOI:10.1002/jcb.21255

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.

(c) 2007 Wiley-Liss, Inc.

MeSH Terms (12)

Animals Fibroblasts Gene Expression Regulation Mice Mice, Knockout Models, Biological Signal Transduction Smad2 Protein Smad3 Protein Transcription, Genetic Transcription Factors Transforming Growth Factor beta

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