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

The TGF-beta superfamily of proteins regulates many different biological pr ocesses, including cell growth, differentiation and embryonic pattern forma tion(1-3). TGF-beta-like factors signal across cell membranes through compl exes of transmembrane receptors known as type I and type II serine/threonin e-kinase receptors, which in turn activate the SMAD signalling pathway(4,5) . On the inside of the cell membrane, a receptor-regulated class of SMADs a re 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-beta target SMADs 2 and 3. Phosphorylation of receptor-regulated SMADs induces their association with Smad4, the 'common-partner' SMAD, and stimulates accumulation of this compl ex in the nucleus, where it regulates transcriptional responses. Here we de scribe Smurf1, a new member of the Hect family of E3 ubiquitin ligases. Smu rf1 selectively interacts with receptor-regulated SMADs specific for the BM P pathway in order to trigger their ubiquitination and degradation, and hen ce their inactivation. In the amphibian Xenopus laevis, Smurf1 messenger RN A is localized to the animal pole of the egg; in Xenopus embryos, ectopic S murf1 inhibits the transmission of BMP signals and thereby affects pattern formation. Smurf1 also enhances cellular responsiveness to the Smad2 (activ in/TGF-beta) pathway. Thus, targeted ubipuitination of SMADs may serve to c ontrol both embryonic development and a wide variety of cellular responses to TGF-beta signals.