Smad Family

SMAD proteins are a unique group of related intracellular proteins responsible for transducing the signal induced by transforming growth factor-β (TGF-β) superfamily into the nucleus. Signals are initiated upon binding of TGF-β superfamily members to cell-surface serine/threonine kinase receptors and are then propagated by Smads. Activation of Smads results in their translocation from the cytoplasm into the nucleus, where they activate or repress transcription together with transcription factors so as to regulate target gene expression.
Functional studies have demonstrated that Smads, which range from about 400 to 500 amino acids in length, can be grouped into three subfamilies, the receptor-regulated Smads (R-Smads, i.e. Smads1/2/3/5/8), the common Smads (co-Smads, i.e. Smad4) and the inhibitory Smads (I-Smads, i.e. Smads6/7), each of which plays a distinct role in the pathway. Specifically, ligand binding induces activation of TGF-β receptor complexes, which then directly phosphorylate (P) specific R-Smads. These R-Smads associate with the co-Smads Smad4 and then translocate to the nucleus, where they interact with a variety of DNA-binding partners to regulate gene expression. Conversely, the I-Smads served to dampen TGF-β signaling in a feedback manner through a variety of mechanisms.