Unique players in the BMP pathway:: Small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling
Unique players in the BMP pathway:: Small C-terminal domain phosphatases dephosphorylate Smad1 to attenuate BMP signaling
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DOI：
10.1073/pnas.0605133103
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发表时间：
2006-08-08
影响因子：
11.1
通讯作者：
Brivanlou, Ali H.
中科院分区：
文献类型：
--
作者：
Knockaert, Marie;Sapkota, Gopal;Brivanlou, Ali H.
Smad转录因子是TGF-β/骨形态发生蛋白（BMP）家族细胞因子和形态发生素的关键信号转导子。TGF-β和BMP膜受体的C-末端丝氨酸磷酸化驱动Smads进入细胞核作为转录调节因子。活化Smads的去磷酸化和再循环是该过程的组成部分，这对于细胞的激动剂感受至关重要。然而，涉及的核磷酸酶仍然未知。在这里，我们提供了功能，生化和胚胎学的证据，确定SCP（小C-末端结构域磷酸酶）家族的核磷酸酶作为介质的Smadl去磷酸化的BMP信号通路在脊椎动物。非洲爪蟾SCP2/Os4抑制假定外胚层中的BMP活性并导致神经化。在非洲爪蟾胚胎中，SCP 2/Os4和人SCP 1，2和3导致选择性去磷酸化Smad1相比，Smad2，抑制BMP和Smad1依赖的转录，并导致诱导的第二背轴。在人类细胞中，SCP1和SCP2的RNAi介导的耗竭增加了响应BMP的Smad1磷酸化的程度和持续时间、Smad1的转录作用和内源性BMP基因响应的强度。目前确定的SCP家族Smad C-末端磷酸酶揭示的事件，减弱Smad信号，并揭示了意想不到的联系，在真核生物中控制RNA聚合酶II的基本磷酸酶。
Smad transcription factors are key signal transducers for the TGF-beta/bone morphogenetic protein (BMP) family of cytokines and morphogens. C-terminal serine phosphorylation by TGF-beta and BMP membrane receptors drives Smads into the nucleus as transcriptional regulators. Dephosphorylation and recycling of activated Smads is an integral part of this process, which is critical for agonist sensing by the cell. However, the nuclear phosphatases involved have remained unknown. Here we provide functional, biochemical, and embryological evidence identifying the SCP (small C-terminal domain phosphatase) family of nuclear phosphatases as mediators of Smadl dephosphorylation in the BMP signaling pathway in vertebrates. Xenopus SCP2/Os4 inhibits BMP activity in the presumptive ectoderm and leads to neuralization. In Xenopus embryos, SCP2/Os4 and human SCP1, 2, and 3 cause selective dephosphorylation of Smad1 compared with Smad2, inhibiting BMP- and Smad1-dependent transcription and leading to the induction of the secondary dorsal axis. In human cells, RNAi-mediated depletion of SCP1 and SCP2 increases the extent and duration of Smadl phosphorylation in response to BMP, the transcriptional action of Smad1, and the strength of endogenous BMP gene responses. The present identification of the SCP family as Smad C-terminal phosphatases sheds light on the events that attenuate Smad signaling and reveals unexpected links to the essential phosphatases that control RNA polymerase II in eukaryotes.