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首页> 外文期刊>Science Signaling >Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner
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Gain-of-function mutations in the gene encoding the tyrosine phosphatase SHP2 induce hydrocephalus in a catalytically dependent manner

机译：在编码酪氨酸磷酸酶SHP2的基因中的功能突变以催化依赖性方式诱导脑积水

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摘要

Catalytically activating mutations in Ptpn11, which encodes the protein tyrosine phosphatase SHP2, cause 50% of Noonan syndrome (NS) cases, whereas inactivating mutations in Ptpn11 are responsible for nearly all cases of the similar, but distinct, developmental disorder Noonan syndrome with multiple lentigines (NSML; formerly called LEOPARD syndrome). However, both types of disease mutations are gain-of-function mutations because they cause SHP2 to constitutively adopt an open conformation. We found that the catalytic activity of SHP2 was required for the pathogenic effects of gain-of-function, disease-associated mutations on the development of hydrocephalus in the mouse. Targeted pan-neuronal knockin of a Ptpn11 allele encoding the active SHP2 E76K mutant resulted in hydrocephalus due to aberrant development of ependymal cells and their cilia. These pathogenic effects of the E76K mutation were suppressed by the additional mutation C459S, which abolished the catalytic activity of SHP2. Moreover, ependymal cells in NSML mice bearing the inactive SHP2 mutant Y279C were also unaffected. Mechanistically, the SHP2 E76K mutant induced developmental defects in ependymal cells by enhancing dephosphorylation and inhibition of the transcription activator STAT3. Whereas STAT3 activity was reduced in Ptpn11(E76K/+) cells, the activities of the kinases ERK and AKT were enhanced, and neural cell-specific Stat3 knockout mice also manifested developmental defects in ependymal cells and cilia. These genetic and biochemical data demonstrate a catalytic-dependent role of SHP2 gain-of-function disease mutants in the pathogenesis of hydrocephalus.
机译：PTPN11中的催化激活突变，其编码蛋白质酪氨酸磷酸酶SHP2，导致50％的日南综合征（NS）案例，而PTPN11中的灭活突变是几乎所有类似但不同的，发育障碍NOONAN综合征与多个母语综合征的原因（NSML;以前称为豹综合征）。然而，两种类型的疾病突变是功能性突变，因为它们导致SHP2组成思考开放构象。我们发现SHP2的催化活性是为了致函数的致病作用，疾病相关突变对小鼠脑积水的发育。靶向泛神经元敲蛋白，其PTPN11等位基因编码活性SHP2 E76K突变体导致脑膜炎突变细胞及其纤毛的异常发育导致脑积水。通过附加突变C459S抑制了E76K突变的这些致病作用，其废除了SHP2的催化活性。此外，携带无活性SHP2突变体Y279C的NSML小鼠中的突变细胞也不受影响。通过提高磷酸化和抑制转录活化剂Stat3，通过提高突变细胞的SHP2 E76K突变体诱导突出细胞的发育缺陷。在PTPN11（E76K / +）细胞中降低了STAT3活性，提高了激酶ERK和AKT的活性，并且神经细胞特异性STAT3敲除小鼠也表现出介质细胞和纤毛的发育缺陷。这些遗传和生物化学数据表明，SHP2函数疾病突变体在脑积水的发病机制中的催化依赖性作用。

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  • 来源
    《Science Signaling》 |2018年第522期|共12页
  • 作者

    Zheng Hong; Yu Wen-Mei; Waclaw Ronald R.; Kontaridis Maria I.; Neel Benjamin G.; Qu Cheng-Kui;

  • 作者单位

    Emory Univ Sch Med Childrens Healthcare Atlanta Aflac Canc &

    Blood Disorders Ctr Dept Pediat Atlanta GA 30322 USA;

    Emory Univ Sch Med Childrens Healthcare Atlanta Aflac Canc &

    Blood Disorders Ctr Dept Pediat Atlanta GA 30322 USA;

    Cincinnati Childrens Hosp Med Ctr Div Expt Hematol Cincinnati OH 45229 USA;

    Harvard Med Sch Beth Israel Deaconess Med Ctr Div Cardiol Dept Med Boston MA 02115 USA;

    NYU Laura &

    Isaac Perlmutter Canc Ctr 550 1St Ave New York NY 10016 USA;

    Emory Univ Sch Med Childrens Healthcare Atlanta Aflac Canc &

    Blood Disorders Ctr Dept Pediat Atlanta GA 30322 USA;

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  • 正文语种 eng
  • 中图分类 细胞生物学;
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