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.
- 1. Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA.
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.