Insulin-like growth factor-I activation of Akt survival cascade in neuronal cells requires the presence of its cognate receptor in caveolae
Insulin-like growth factor-I activation of Akt survival cascade in neuronal cells requires the presence of its cognate receptor in caveolae
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DOI：
10.1016/j.yexcr.2007.10.013
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发表时间：
2008-01-15
影响因子：
3.7
通讯作者：
Seo, Hisao
中科院分区：
文献类型：
--
作者：
Lu, Xiui;Kambe, Fukushi;Seo, Hisao
胰岛素样生长因子-I（IGF-I）在神经元存活中起重要作用。小窝是细胞膜上富含胆固醇的微区，是某些神经营养因子的平台。在这项研究中，我们研究了在嗜铬细胞瘤PC 12细胞的IGF-I信号转导的小窝的可能作用。IGF-I治疗减弱血清戒断诱导的细胞凋亡，这是逆转的治疗与甲基-β-环糊精（CD），从质膜上去除胆固醇。免疫细胞化学和亚细胞分级分析表明，IGF-I受体（IGF-IR）与小窝蛋白-1，在小窝的主要蛋白质组分共定位，CD治疗减少IGF-IR内容在小窝。与这些发现一致，胰岛素受体底物-1和Akt的IGF-I磷酸化受损，胆固醇供应恢复IGF-I作用。此外，使用小干扰RNA的实验表明，小窝蛋白-1表达的减少损害了IGF-I的作用。此外，IGF-IR与小窝蛋白-1的共定位，以及小窝依赖性IGF-I的作用在大鼠小脑颗粒神经元的原代培养中被复制。这些结果表明，小窝中IGF-IR的存在是IGF-I的神经保护作用所必需的。(C)2007爱思唯尔公司All rights reserved.
Insulin-like growth factor-I (IGF-I) plays important roles in survival of neurons. Caveolae, cholesterol-rich microdomains of plasma membrane, act as platforms for some neurotrophic factors. In this study, we examined a possible role of caveolae in IGF-I signal transduction in pheochromocytoma PC12 cells. IGF-I treatment attenuated serum withdrawal-induced apoptosis, which was reversed by treatment with methyl-beta-cyclodextrin (CD) that removes cholesterol from plasma membrane. Immunocytochemical and subcellular fractionation analyses revealed that IGF-I receptor (IGF-IR) was colocalized with caveolin-1, a major protein component in caveolae, and that CD treatment reduced IGF-IR contents in caveolae. Consistent with these findings, IGF-I phosphorylation of insulin receptor substrate-1 and Akt was impaired, and cholesterol supply restored the IGF-I action. Furthermore, experiments using small interfering RNA revealed that the reduction of caveolin-1 expression impaired the IGF-I action. In addition, the colocalization of IGF-IR with caveolin-1, and the caveolae-dependent IGF-I action were duplicated in primary culture of rat cerebellar granule neurons. These results demonstrate that the presence of IGF-IR in caveolae is required for the neuroprotective action of IGF-I. (C) 2007 Elsevier Inc. All rights reserved.