How the Smads regulate transcription.
The primary signalling pathway downstream of ligands of the transforming growth factor beta (TGF-beta) superfamily is the Smad pathway. Activated receptors phosphorylate receptor-regulated Smads, which form homomeric complexes and heteromeric complexes with Smad4. These activated Smad complexes accumulate in the nucleus, where they are directly involved in the regulation of transcription of target genes. This apparently very simple pathway is subject to complex regulation, much of which is at the level of post-translational modifications of pathway components, in particular, the Smads. The enzymes responsible may be constitutively active, may be cell type-specific or may be regulated by other signalling pathways or by the cell cycle. In this way, signals from TGF-beta superfamily ligands are integrated with signals from other growth factors and cytokines, are regulated by the cell cycle and are dependent on cell type. This may go some way to explaining the pleiotropic nature of TGF-beta superfamily responses. In this review we focus on the mechanisms whereby the Smads are modified and regulated. We then go on to discuss how the activated Smad complexes regulate transcription.
Ross
Sarah
S
Laboratory of Developmental Signalling, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, United Kingdom.
Hill
Caroline S
CS
D000818:Animals; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D020929:Mitogen-Activated Protein Kinase Kinases