The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2-and Src-Dependent Manner
The Neurofibromatosis 2 Protein, Merlin, Regulates Glial Cell Growth in an ErbB2-and Src-Dependent Manner
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DOI：
10.1128/mcb.01392-08
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发表时间：
2009-03-15
影响因子：
5.3
通讯作者：
Gutmann, David H.
中科院分区：
文献类型：
--
作者：
Houshmandi, S. Sean;Emnett, Ryan J.;Gutmann, David H.
患有遗传性癌症易感综合征2型神经纤维瘤病（NF 2）的个体会发生几种中枢神经系统（CNS）恶性肿瘤，包括神经胶质细胞肿瘤（室管膜瘤）。最近的研究表明，NF 2蛋白，梅林（或神经鞘蛋白），可调节受体酪氨酸激酶信号，细胞内促有丝分裂生长控制途径，或在非神经系统细胞类型的粘附连接组织。在本报告中，我们使用胶质细胞酸性蛋白条件性基因敲除小鼠和衍生的胶质细胞来确定梅林如何调节中枢神经系统胶质细胞增殖。我们发现，在体外和体内的神经胶质细胞中的梅林的损失的结果增加增殖。Merlin对神经胶质细胞生长的调节反映了Src活性的失调，从而Src活化的药理学或遗传学抑制将Nf 2（-/-）神经胶质细胞生长降低至野生型水平。我们进一步表明，Src调节NF 2（-/-）神经胶质细胞的生长顺序调节FAK和桩蛋白磷酸化/活性。接下来，我们证明了Src激活是由ErbB 2激活的梅林调节引起的，并且遗传或药理学ErbB 2抑制将Nf 2（-/-）神经胶质细胞Src/Src效应子激活和增殖降低至野生型水平。最后，我们表明，梅林竞争与Src的直接结合ErbB 2和梅林调控ErbB 2依赖的Src信号和生长控制提出了一种新的分子机制。
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.