A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation

• Published in: Nature (London) Vol. 400; no. 6745; pp. 687 - 693
• Main Authors: Thomsen, Gerald H, Zhu, Haitao, Kavsak, Peter, Abdollah, Shirin, Wrana, Jeffrey L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 12.08.1999; Nature Publishing Group
• Subjects: Animals; Bacteria; Biological and medical sciences; Body Patterning - physiology; Bone Morphogenetic Proteins - metabolism; Cell Line; Cellular biology; Classical genetics, quantitative genetics, hybrids; Cloning, Molecular; COS Cells; DNA-Binding Proteins - metabolism; Ectoderm - metabolism; Embryo, Nonmammalian - metabolism; Embryonic growth stage; Fundamental and applied biological sciences. Psychology; Genetics of eukaryotes. Biological and molecular evolution; Humans; Inactivation; Ligases - genetics; Ligases - metabolism; Membranes; Molecular Sequence Data; Phosphoproteins - metabolism; Proteins; Signal Transduction; Smad Proteins; Smad2 Protein; Smad5 Protein; Trans-Activators - metabolism; Transforming Growth Factor beta - metabolism; Ubiquitin-Protein Ligases; Ubiquitins - metabolism; Vertebrata; Xenopus; Xenopus laevis; Xenopus Proteins; Yeast; Embryonic development; Embryo; Carbon-nitrogen ligases; Nucleotide sequence; Enzyme; Xenopus laevis; Amphibia; Molecular interaction; Salientia; Gene expression; Signal transduction; Vertebrata; Bone morphogenetic protein; Gene; Ligases; Proteolysis; Localization; Ubiquitin-protein ligase; Biological receptor
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/23293

The TGF-β superfamily of proteins regulates many different biological processes, including cell growth, differentiation and embryonic pattern formation. TGF-β-like factors signal across cell membranes through complexes of transmembrane receptors known as type I and type II serine/threonine-kinase receptors, which in turn activate the SMAD signalling pathway,. On the inside of the cell membrane, a receptor-regulated class of SMADs are phosphorylated by the type-I-receptor kinase. In this way, receptors for different factors are able to pass on specific signals along the pathway: for example, receptors for bone morphogenetic protein (BMP) target SMADs 1, 5 and 8, whereas receptors for activin and TGF-β target SMADs 2 and 3. Phosphorylation of receptor-regulated SMADs induces their association with Smad4, the 'common-partner' SMAD, and stimulates accumulation of this complex in the nucleus, where it regulates transcriptional responses. Here we describe Smurf1, a new member of the Hect family of E3 ubiquitin ligases. Smurf1 selectively interacts with receptor-regulated SMADs specific for the BMP pathway in order to trigger their ubiquitination and degradation, and hence their inactivation. In the amphibian Xenopus laevis, Smurf1 messenger RNA is localized to the animal pole of the egg; in Xenopus embryos, ectopic Smurf1 inhibits the transmission of BMP signals and thereby affects pattern formation. Smurf1 also enhances cellular responsiveness to the Smad2 (activin/TGF-β) pathway. Thus, targeted ubiquitination of SMADs may serve to control both embryonic development and a wide variety of cellular responses to TGF-β signals.