TGF-beta (Transforming Growth Factor-beta) cytokines employ Smad proteins as the 
intracellular mediator of signaling. Upon TGF-beta stimulation, the cytoplasmic 
Smads become phosphorylated and consequently accumulate in the nucleus to 
regulate target gene expression. The cytoplasm-to-nucleus redistribution of 
Smads, as well as the ability of Smads to activate or repress gene 
transcription, is under multiple layers of regulation by factors not limited to 
TGF-beta. With recent advance in the knowledge of regulatory factors impinged on 
Smads, we are beginning to understand the complexity in cellular responses to 
TGF-beta.