TGFβ Signaling: Receptors, Transducers, and Mad Proteins

nant type I receptor in vitro (references can be found The transforming growth factor b (TGFb) family of cytoin Massagué and Weis-Garcia, 1996). Phosphorylation kines regulates cell proliferation, differentiation, recogoccurs in a cluster of five serine and threonine residues nition, and death and figures prominently in the control in the GS domain, a highly conserved region next to the of development, tissue recycling, and repair. The singuN-terminus of the kinase domain in all type I receptors. larity of the mechanisms that mediate these effects beMutation of these residues obstructs signaling, the secame manifest with the discovery, a few years ago, that verity of this defect being proportional to the number of their membrane receptors are serine/threonine kinases. mutated residues. The type II receptors have kinase This property sets them apart from other major classes activity that does not seem to be augmented by ligand of hormone receptors. New insights into the mechanism binding. In essence, the ligand may be acting as an of receptor activation and the implication of the Mad adaptor that brings a substrate—the type I receptor—to (Mothers against dpp) gene family in TGFb signal transthe primary receptor kinase. duction emphasize the uniqueness of this signaling Key support for the idea that type I receptors act network. downstream of the type II receptors is provided by the