Negative regulation of TGF-β receptor/Smad signal transduction

Members of the transforming growth factor-beta (TGF-beta) family are highly conserved multifunctional cell-cell signaling proteins that are of key importance for controlling embryogenesis and tissue homeostasis. At first glance, signaling through TGF-beta family members appears to be a simple process: ligands bind to specific serine/threonine kinase transmembrane receptors, which activate intracellular Smad effector proteins, which in turn relay the signal to the nucleus to control gene transcription. However, recent research has revealed that additional layers of complexity exist at each step in the TGF-beta/Smad pathway. The expression, activation and inactivation, subcellular localization, and stability of TGF-beta signaling components are tightly regulated and subject to input from other signaling pathways. A broad array of Smad interacting partners and diverse post-translational modifications of Smads have been identified. Recently, important advances have been made in our understanding of how TGF-beta family signals are attenuated and terminated to maintain control over this versatile pathway.