Sterol structure dependence of insulin receptor and insulin-like growth factor 1 receptor activation
Sterol structure dependence of insulin receptor and insulin-like growth factor 1 receptor activation
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DOI：
10.1016/j.bbamem.2019.01.009
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发表时间：
2019-04-01
影响因子：
3.4
通讯作者：
Miller, W. Todd
中科院分区：
文献类型：
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作者：
Delle Bovi, Richard J.;Kim, JiHyun;Miller, W. Todd
质膜是一个动态环境，具有脂质、蛋白质和胆固醇的复杂组成。富含胆固醇和鞘脂的区域被认为形成脂筏，高度有序的脂质结构域。这些域的独特物理性质已经被提出来影响许多细胞过程。在这里，我们证明了胰岛素受体（IR）和胰岛素样生长因子1受体（IGF 1 R）的激活关键取决于膜甾醇的结构。IR和IGF 1 R在体内的自磷酸化被胆固醇耗竭抑制，并且自磷酸化被外源性胆固醇替代恢复。我们接下来筛选了各种甾醇对IR活化的影响。甾醇支持IR自磷酸化的能力与甾醇形成有序结构域的倾向密切相关。IR自磷酸化完全恢复麦角甾醇，二氢胆固醇，7-脱氢胆固醇，脂甾醇，链甾醇，和别胆固醇的掺入，部分恢复表胆甾醇，并没有恢复羊毛甾醇，粪甾烷醇，和4-甾烯-3-酮。这些数据支持的假设，即形成有序结构域的能力是足够的甾醇，以支持完整的哺乳动物细胞中的IR和IGF 1 R的配体诱导的激活。
The plasma membrane is a dynamic environment with a complex composition of lipids, proteins, and cholesterol. Areas enriched in cholesterol and sphingolipids are believed to form lipid rafts, domains of highly ordered lipids. The unique physical properties of these domains have been proposed to influence many cellular processes. Here, we demonstrate that the activation of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) depends critically on the structures of membrane sterols. IR and IGF1R autophosphorylation in vivo was inhibited by cholesterol depletion, and autophosphorylation was restored by the replacement with exogenous cholesterol. We next screened a variety of sterols for effects on IR activation. The ability of sterols to support IR autophosphorylation was strongly correlated to the propensity of the sterols to form ordered domains. IR autophosphorylation was fully restored by the incorporation of ergosterol, dihydrocholesterol, 7-dehydrocholesterol, lathosterol, desmosterol, and allocholesterol, partially restored by epicholesterol, and not restored by lanosterol, coprostanol, and 4-cholesten-3-one. These data support the hypothesis that the ability to form ordered domains is sufficient for a sterol to support ligand-induced activation of IR and IGF1R in intact mammalian cells.