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首页> 外文期刊>Molecular and Cellular Biology >The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner
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The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2- and Src-Dependent Manner

机译：Neurofibromatosis 2蛋白，Merlin，以ErbB2和Src依赖性的方式调节胶质细胞的生长。

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Individuals with the inherited cancer predisposition syndrome neurofibromatosis 2 (NF2) develop several central nervous system (CNS) malignancies, including glial cell neoplasms (ependymomas). Recent studies have suggested that the NF2 protein, merlin (or schwannomin), may regulate receptor tyrosine kinase signaling, intracellular mitogenic growth control pathways, or adherens junction organization in non-nervous-system cell types. For this report, we used glial fibrillary acidic protein conditional knockout mice and derivative glia to determine how merlin regulates CNS glial cell proliferation. We show that the loss of merlin in glial cells results in increased proliferation in vitro and in vivo. Merlin regulation of glial cell growth reflects deregulated Src activity, such that pharmacologic or genetic inhibition of Src activation reduces Nf2?/? glial cell growth to wild-type levels. We further show that Src regulates Nf2?/? glial cell growth by sequentially regulating FAK and paxillin phosphorylation/activity. Next, we demonstrate that Src activation results from merlin regulation of ErbB2 activation and that genetic or pharmacologic ErbB2 inhibition reduces Nf2?/? glial cell Src/Src effector activation and proliferation to wild-type levels. Lastly, we show that merlin competes with Src for direct binding to ErbB2 and present a novel molecular mechanism for merlin regulation of ErbB2-dependent Src signaling and growth control.
机译：具有遗传易感性综合征神经纤维瘤病2（NF2）的个体会发展出几种中枢神经系统（CNS）恶性肿瘤，包括神经胶质细胞瘤（室管膜瘤）。最近的研究表明， NF2 蛋白，merlin（或schwannomin），可能调节非神经系统细胞类型中的受体酪氨酸激酶信号传导，细胞内有丝分裂生长控制途径或粘附连接组织。对于此报告，我们使用了神经胶质纤维酸性蛋白条件敲除小鼠和衍生神经胶质细胞来确定merlin如何调节CNS神经胶质细胞增殖。我们表明神经胶质细胞中merlin的损失导致体外和体内增殖的增加。 Merlin对神经胶质细胞生长的调节反映了Src活性的失调，因此药理或遗传抑制Src激活可将 Nf2 ？/？神经胶质细胞生长降低至野生型水平。我们进一步表明，Src通过依次调节FAK和paxillin磷酸化/活性来调节 Nf2 ？/？胶质细胞的生长。接下来，我们证明Src激活是由Merlin调控的ErbB2激活引起的，并且遗传或药理作用的ErbB2抑制作用会降低 Nf2 ？/？胶质细胞Src / Src效应子的激活和增殖野生型水平。最后，我们表明merlin与Src竞争直接结合到ErbB2，并提出了Merlin调节ErbB2依赖性Src信号传导和生长控制的新型分子机制。

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