12 Regulation of TGF-β Family Signaling by Inhibitory Smads

Abstract

TGF-β family signaling is regulated through multiple mechanisms, and its magnitude is finely tuned by various positive and negative regulators (Miyazono 2000). Although negative signal regulators are present in other signaling pathways, the TGF-β family signaling systems may be unique, because some of these negative regulators are structurally similar to components of TGF-β family signals. It should also be noted that TGF-β family signaling itself induces expression of most of these negative regulators in many different types of cells, and that the negative regulators in turn modulate such signaling through negative feedback loops. Lefty1 and lefty2 are proteins with cystine-knot motifs and are structurally related to the TGF-β family ligands, although they do not form dimers (Meno et al. 1999; Thisse and Thisse 1999). Lefty binds to activin receptors and competes with activins for receptor binding. Inhibins are composed of α-chain and β-chain dimers and antagonize the effects of activins composed of β-chain dimers (see Chapter 4). BAMBI (BMP and activin membrane-bound inhibitor) is a transmembrane protein whose extracellular and transmembrane domains are structurally similar to type I receptors, although it lacks an intracellular domain (Onichtchouk et al. 1999). BAMBI interacts with type I receptors, but is unable to transduce intracellular signals. Inhibitory Smads (I-Smads) are members of the Smad family with conserved carboxy-terminal MH2 domains, which interact with activated type I receptors and receptor-activated Smads (R-Smads) and inhibit intracellular signaling. The activities of I-Smads are intriguing, because, in addition to inhibiting the Smad-mediated signaling by negative feedback mechanisms, they...