Zhu H, Kavsak P, Abdollah S, Wrana J L, Thomsen G H
Department of Biochemistry and Cell Biology and Institute for Cell and Developmental Biology, State University of New York, Stony Brook 11794-5215, USA.
Nature. 1999 Aug 12;400(6745):687-93. doi: 10.1038/23293.
The TGF-beta superfamily of proteins regulates many different biological processes, including cell growth, differentiation and embryonic pattern formation. TGF-beta-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-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 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-beta) pathway. Thus, targeted ubiquitination of SMADs may serve to control both embryonic development and a wide variety of cellular responses to TGF-beta signals.
转化生长因子-β（TGF-β）超家族蛋白调节许多不同的生物学过程，包括细胞生长、分化和胚胎模式形成。TGF-β样因子通过被称为I型和II型丝氨酸/苏氨酸激酶受体的跨膜受体复合物跨细胞膜发出信号，这些受体进而激活SMAD信号通路。在细胞膜内侧，一类受体调节型SMAD被I型受体激酶磷酸化。通过这种方式，不同因子的受体能够沿着该通路传递特定信号：例如，骨形态发生蛋白（BMP）的受体靶向SMAD 1、5和8，而激活素和TGF-β的受体靶向SMAD 2和3。受体调节型SMAD的磷酸化诱导它们与“共同伙伴”SMAD即Smad4缔合，并刺激该复合物在细胞核中积累，在细胞核中它调节转录反应。在此，我们描述了Smurf1，一种E3泛素连接酶的Hect家族的新成员。Smurf1选择性地与BMP通路特有的受体调节型SMAD相互作用，以触发它们的泛素化和降解，从而使其失活。在两栖动物非洲爪蟾中，Smurf1信使核糖核酸定位于卵的动物极；在爪蟾胚胎中，异位表达的Smurf1抑制BMP信号的传递，从而影响模式形成。Smurf1还增强细胞对Smad2（激活素/TGF-β）通路的反应性。因此，SMAD的靶向泛素化可能有助于控制胚胎发育以及对TGF-β信号的多种细胞反应。
