Gerdøe-Kristensen Stine, Lund Viktor K, Wandall Hans H, Kjaerulff Ole
Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen N, Denmark.
J Cell Physiol. 2017 Nov;232(11):3112-3127. doi: 10.1002/jcp.25762. Epub 2017 Mar 31.
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.
受体酪氨酸激酶（RTK）信号传导控制细胞分化、增殖、存活、代谢和迁移的关键方面。RTK信号传导失调也是许多癌症的基础。糖鞘脂（GSL）是质膜的重要组成部分。通过影响膜受体的聚集和活性，GSL调节信号转导，包括由RTK介导的信号转导。GSL在神经系统中含量丰富，果蝇中的神经胶质发育正在成为研究GSL如何调节RTK信号传导的有用模型。果蝇有一个简单的GSL生物合成途径，其中甘露糖基转移酶Egghead控制葡萄糖神经酰胺（GlcCer）向乳糖神经酰胺（MacCer）的转化。Egghead（egh）突变体中缺乏延长的GSL会导致神经周膜下神经胶质细胞（SPG）过度生长，这主要是由于磷脂酰肌醇3激酶（PI3K）的异常激活。然而，这种效应在多大程度上涉及上游信号事件的变化尚未解决。我们在此表明，egh中的神经胶质过度生长与胰岛素和成纤维细胞生长因子受体（FGFR）的激活增加密切相关。当在野生型SPG中过表达果蝇胰岛素受体（InR）和FGFR同源物无心脏（Htl）的功能获得性突变体时，会出现神经胶质肥大现象，而在egh中抑制Htl和InR活性可抑制这种现象。在SPG中敲低GlcCer合酶不能抑制egh神经中的神经胶质过度生长，反而在野生型中略有促进过度生长，这表明RTK的过度激活是由MacCer的缺失而非GlcCer的积累引起的。我们得出结论，GSL生物合成中的早期产物MacCer可防止果蝇神经胶质中胰岛素和成纤维细胞生长因子受体的不适当激活。
