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首页> 外文期刊>Journal of Cellular Physiology >Mactosylceramide prevents glial cell overgrowth by inhibiting insulin and fibroblast growth factor receptor signaling
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Mactosylceramide prevents glial cell overgrowth by inhibiting insulin and fibroblast growth factor receptor signaling

机译：Mactosylceramide防止胶质细胞增生抑制胰岛素和纤维母细胞生长因子受体信号

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摘要

Receptor tyrosine kinase (RTK) signaling controls key aspects of cellular differentiation, proliferation, survival, metabolism, and migration. Deregulated RTK signaling also underlies many cancers. Glycosphingolipids (GSL) are essential elements of the plasma membrane. By affecting clustering and activity of membrane receptors, GSL modulate signal transduction, including that mediated by the RTK. GSL are abundant in the nervous system, and glial development in Drosophila is emerging as a useful model for studying how GSL modulate RTK signaling. Drosophila has a simple GSL biosynthetic pathway, in which the mannosyltransferase Egghead controls conversion of glucosylceramide (GlcCer) to mactosylceramide (MacCer). Lack of elongated GSL in egghead (egh) mutants causes overgrowth of subperineurial glia (SPG), largely due to aberrant activation of phosphatidylinositol 3-kinase (PI3K). However, to what extent this effect involves changes in upstream signaling events is unresolved. We show here that glial overgrowth in egh is strongly linked to increased activation of Insulin and fibroblast growth factor receptors (FGFR). Glial hypertrophy is phenocopied when overexpressing gain-of-function mutants of the Drosophila insulin receptor (InR) and the FGFR homolog Heartless (Htl) in wild type SPG, and is suppressed by inhibiting Htl and InR activity in egh. Knockdown of GlcCer synthase in the SPG fails to suppress glial overgrowth in egh nerves, and slightly promotes overgrowth in wild type, suggesting that RTK hyperactivation is caused by absence of MacCer and not by GlcCer accumulation. We conclude that an early product in GSL biosynthesis, MacCer, prevents inappropriate activation of insulin and fibroblast growth factor receptors in Drosophila glia.
机译：受体酪氨酸激酶(RTK)信号控制细胞分化的关键方面,增殖、存活、代谢和迁移。很多癌症。质膜的元素是必不可少的。影响聚类和膜的活性GSL调节信号转导受体,包括RTK介导的。丰富的神经系统和神经胶质果蝇是发展成为一个有用的模型研究GSL调节RTK信号。生物合成途径,mannosyltransferase书呆子控制转换mactosylceramide葡糖神经酰胺(相关)(mac)。突变导致subperineurial神经胶质增生(SPG),很大程度上是由于异常的激活磷脂酰肌醇3-kinase (PI3K)。多大程度上影响涉及的变化上游信号事件没有得到解决。在这里,在egh强烈胶质增生与激活胰岛素和增加纤维母细胞生长因子受体(FGFR)。当overexpressing肥大是拟表型功能果蝇的突变体胰岛素受体(InR)和FGFR同族体无情(Htl)野生型厂家,抑制通过抑制Htl和InR活动egh。未能抑制egh神经胶质增生,在野生型略有促进生长,这表明RTK hyperactivation所致没有mac而不是相关积累。我们得出结论,在GSL早期产品生物合成,mac,防止不适当激活胰岛素和纤维母细胞生长在果蝇神经胶细胞因子受体。

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