Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways.
Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways.
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去磷酸化的parafibromin是Wnt/HedgeHog/Notch途径的转录共激活因子。
DOI：
10.1038/ncomms12887
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发表时间：
2016-09-21
影响因子：
16.6
通讯作者：
Hatakeyama, Masanori
中科院分区：
文献类型：
--
作者：
Kikuchi, Ippei;Takahashi-Kanemitsu, Atsushi;Sakiyama, Natsuki;Tang, Chao;Tang, Pei-Jung;Noda, Saori;Nakao, Kazuki;Kassai, Hidetoshi;Sato, Toshiro;Aiba, Atsu;Hatakeyama, Masanori
进化上保守的Wnt、Hedgehog(HH)和Notch形态原通路在多细胞生物的发育、动态平衡和发病机制中发挥着重要作用。然而，细胞内协调这些信号输入的机制仍然知之甚少。在这里，我们发现PAF复合体的一个成分副纤维蛋白与β-连环蛋白和Gli1竞争性地相互作用，从而以一种相互排斥的方式增强WNT-和HH-靶基因的反式激活。副纤维蛋白还与Notch胞内域(NICD)结合，使Wnt-和Notch-靶基因能够协同激活。SHP2磷酸酶介导的酪氨酸去磷酸化增强副纤维蛋白的转录平台功能，而PTK6激酶介导的酪氨酸磷酸化减弱副纤维蛋白的转录平台功能。因此，小鼠的副纤维蛋白的急性丢失会破坏肠道的正常上皮结构，这需要Wnt、HH和/或Notch信号的协调激活/失活。副纤维蛋白以酪氨酸磷酸化/去磷酸化调控的方式整合和转换由这些形态发生途径传递的信号，并将其转化为适当的转录输出。正常的肠上皮组织需要Wnt和Hedgehog的信号活动。在这里，作者表明，副纤维蛋白可以以一种相互排斥的方式激活这两条途径，并且对肠道内环境稳定很重要。
Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner. Normal epithelial intestine organisation requires Wnt and Hedgehog signalling activity. Here, the authors show that parafibromin can activate both pathways in a mutually exclusive manner and is important for intestinal homeostasis.
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影响因子：
64.5
作者：
Ouspenskaia T;Matos I;Mertz AF;Fiore VF;Fuchs E
通讯作者：
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通讯作者：
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作者：
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Robine, S