SIGNAL-TRANSDUCTION AND TGF-BETA SUPERFAMILY RECEPTORS

The TGF-beta superfamily includes a large number of related growth and differentiation factors expressed in virtually all phyla. Superfamily members bind to specific cell surface receptors that activate signal transduction mechanisms to elicit their effects. Candidate receptors f all into two primary groups, termed type I and type II receptors. Both types are serine/threonine kinases. Upon activation by the appropriat e ligand, type I and type II receptors physically interact to form het ero-oligomers and subsequently activate intracellular signaling cascad es, ultimately regulating gene transcription and expression. In additi on, TGF-beta binds to a third receptor class, type III, a membrane-anc hored proteoglycan lacking the kinase activity typical of signal trans ducing molecules. Type III receptors appear to regulate ligand availab ility to type I and type II receptors. Although a number of transducti on mechanisms may be available to TGF-beta superfamily members, eviden ce gathered through the use of specific kinase and G-protein inhibitor s and through assays measuring activation and levels of signaling inte rmediates suggests that at least one signaling pathway interacts with Ras and Raf proteins via a G-protein intermediate. Raf begins the cyto plasmic kinase cascade that leads to gene regulation. The myriad respo nses regulated by TGF-beta superfamily members makes the understanding of signal transduction mechanisms utilized by these proteins of great interest to a wide range of biological disciplines.