SMADs are a group of intracellular proteins that deliver extracellular signals from transforming growth factor beta (TGF β) ligands to the nucleus leading the activation of downstream gene transcription to regulate cell growth and division processes.
SMADs are a class of proteins which share similar structures, namely, the highly conserved amino (MH1) and carboxy-terminal (MH2) domains, as well as the less conserved linker region in the middle. Based on structure as well as function, the SMADs can be divided into three major classes: R-SMADs (receptor activated SMADs), Co-SMADs (common SMADs), and I-SMADs (inhibitory SMADs). R-SMADs are consisting of SMADs1, 2, 3, 5, and 8. Co-SMADs are consisting of SMADs4. I-SMADs are consisting of SMAD6 and SMAD7. R-SMADs function as the direct substrates for the type I receptor, and are activated through phosphorylation on a conserved C-terminal SSXS motif. The activation of specific R-SMADs depend, in part, on the active ligands; SMAD2 and SMAD3 transduce TGF-βs, Activin, and Nodal signals while SMAD1, SMAD5, and SMAD8 are activated by BMPs. Once activated, the R-SMADs recruit a Co-SMAD (which is SMAD4 in mammals) to form heteroligomers, which then translocate into the nucleus, bind to target promoters, and recruit coactivators such as p300/CBP to activate transcription. Contrary to R-SMADs and Co-SMADs, which positively propagate TGF-β signals, SMAD6 and SMAD7, known as the I-SMADs, antagonize TGF-β signaling. This is done by blocking RSMAD/Co-SMAD4 association as a SMAD4 decoy, or by masking and further targeting the receptor for degradation, respectively.
One question concerning TGF-β signaling is how a simple pathway elicits such diverse cellular responses. Smif was first identified as a SMAD4 interacting factor by yeast two-hybrid screening. The Human Smif (hSmif) gene yields a 7kb transcript which encodes a 70KD protein. Smif homologues are also present in mouse, zebrafish and Drosophila genomes. It is expressed in almost all human tissues and in mouse embryos from E7–E17. The interaction of Smif with SMAD4 is highly specific in that Smif does not bind with other SMADs. Upon TGF-β or BMP stimulation, Smif associates with SMAD4 and the protein complex translocates into the nucleus. Consistent with the early embryonic ex