Can't get no SMADisfaction: Smad proteins as positive and negative regulators of TGF‐β family signals

: The identification of Smad proteins as molecular components of the transforming growth factor-beta (TGF-beta) signaling cascade has enhanced our understanding of how ligand-mediated activation of TGF-beta receptors leads to modulation of target gene transcription. Recent studies have identified a distinct, structurally related class of Smads which inhibits, rather than transduces, TGF-beta family signals. The molecular mechanism of action and the exact signaling pathways that are targeted by antagonistic Smads are not completely understood. These proteins appear to participate in autoregulatory negative feedback loops in which signaling initiated by specific TGF-beta family ligands induces the expression of an inhibitory Smad that then functions to modulate the amplitude or duration of signaling. Negative feedback circuits such as these play important roles in fine-tuning the activity of multifunctional signaling molecules during embryonic patterning and in response to pathologic stimuli in adults.