Members of the SMAD family of signal transduction molecules are components of a critical intracellular pathway that transmit TGF-β signals from the cell surface into the nucleus. Three distinct classes of SMADs have been defined: the receptor-regulated SMADs, which include SMAD1, 2, 3, 5, and 9; the common-mediator SMAD, SMAD4; and the antagonistic or inhibitory SMADs, SMAD6 and 7. Activated type I receptors associate with specific R-SMADs and phosphorylate them on a conserved carboxy-terminal SSXS motif. The phosphorylated R-SMADs dissociate from the receptor and form a heteromeric complex with SMAD4, initiating translocation of the heteromeric SMAD complex to the nucleus. Once in the nucleus, SMADs recruit a variety of DNA binding proteins that function to regulate transcriptional activity.Following stimulation by TGF-β, Smad2 and Smad3 become phosphorylated at carboxyl terminal serine residues by TGF-β Receptor I. Phosphorylated Smad 2/3 can complex with Smad4 and translocate to the nucleus to regulate gene expression.
[1] Heldin, C.H. et al. (1997) Nature 390, 465-71.
[2] Attisano, L. and Wrana, J.L. (1998) Curr Opin Cell Biol 10, 188-94.
[3] Derynck, R. et al. (1998) Cell 95, 737-40.
[4] Massagué, J. (1998) Annu Rev Biochem 67, 753-91.
[5] Whitman, M. (1998) Genes Dev 12, 2445-62.
[6] Wrana, J.L. (2000) Sci STKE 2000, re1.
[7] Attisano, L. and Wrana, J.L. (2002) Science 296, 1646-7.
[8] Moustakas, A. et al. (2001) J Cell Sci 114, 4359-69.
[9] Abdollah, S. et al. (1997) J. Biol. Chem. 272, 27678-27685.
[10] Souchelnytskyi, S. et al. (1997) J. Biol. Chem. 272, 28107-28115.
