Signal transduction by bone morphogenetic protein receptors: Functional roles of Smad proteins

Intracellular signals for bone morphogenetic proteins (BMPs) and other members in the transforming growth factor (TGF)-beta superfamily are mediated by Smad proteins, Receptor-regulated Smads (R-Smads) are activated by serine/threonine kinase receptors upon ligand binding. R-Smads then form hetero-oligomeric complexes with a common-mediator Smad (co-Smad) and translocate into the nucleus, where they regulate transcription of target genes. Smads 1, 5, and 8 are R-Smads activated by BMP receptor, whereas Smads 2 and 3 are activated by TGF-beta and activin receptors. Smad4 is the only co-Smad isolated in mammals, and is shared by BMP and TGF-beta/activin signaling pathways, Smads 6 and 7 are anti-Smads, which block signals by preventing the activation of R-Smads by serine/threonine kinase receptors, Anti-Smads are induced by ligand stimulation, suggesting that they constitute a negative feedback loop in the signal transduction pathways of the TGF-beta superfamily. (C) 1999 by Elsevier Science Inc. All rights reserved.