Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation.
Cryptochromes regulate IGF-1 production and signaling through control of JAK2-dependent STAT5B phosphorylation.
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DOI：
10.1091/mbc.e16-08-0624
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发表时间：
2017-03-15
影响因子：
3.3
通讯作者：
Kondratov R
中科院分区：
文献类型：
--
作者：
Chaudhari A;Gupta R;Patel S;Velingkaar N;Kondratov R
生物钟通过称为隐花色素的蛋白质调节IGF-1的产生和信号传导，隐花色素调节转录因子STAT 5 B的活性并控制小鼠身体和器官大小。胰岛素样生长因子（IGF）信号传导在细胞生长和增殖中起重要作用，并且与癌症、代谢和衰老的调节有关。在这里，我们报告，IGF-1水平在血液和IGF-1信号表现出昼夜节律。昼夜节律的控制是通过隐花色素（cryptochromes，缩写为CRs）--转录抑制因子和生物钟的组成部分来实现的。Cry缺陷小鼠中的IGF-1节律被破坏，并且这些小鼠中的IGF-1水平降低了80%，这导致IGF信号传导减少。与此一致，Cry缺陷小鼠具有减小的身体（减小约30%）和器官大小。Cry缺乏时IGF-1的下调与肝脏和骨骼肌中Igf-1 mRNA表达的降低相关。Igf-1的转录通过生长素诱导的JAK 2激酶介导的转录因子STAT 5 B磷酸化来调节。在Cry缺陷小鼠的肝脏和骨骼肌中，JAK 2依赖性Y 699位点上的STAT 5 B磷酸化显著降低。与此同时，JAK 2激酶的磷酸化在Cry缺陷时没有减少，这将CRY活性置于JAK 2的下游。因此，胰岛素通过控制STAT 5 B磷酸化将生物钟和JAK-STAT信号传导联系起来，这为体内IGF信号传导的昼夜节律提供了机制。
The circadian clock regulates IGF-1 production and signaling through proteins called cryptochromes, which regulate the activity of transcriptional factor STAT5B and control mouse body and organ size. Insulin-like growth factor (IGF) signaling plays an important role in cell growth and proliferation and is implicated in regulation of cancer, metabolism, and aging. Here we report that IGF-1 level in blood and IGF-1 signaling demonstrates circadian rhythms. Circadian control occurs through cryptochromes (CRYs)—transcriptional repressors and components of the circadian clock. IGF-1 rhythms are disrupted in Cry-deficient mice, and IGF-1 level is reduced by 80% in these mice, which leads to reduced IGF signaling. In agreement, Cry-deficient mice have reduced body (∼30% reduction) and organ size. Down-regulation of IGF-1 upon Cry deficiency correlates with reduced Igf-1 mRNA expression in the liver and skeletal muscles. Igf-1 transcription is regulated through growth hormone–induced, JAK2 kinase–mediated phosphorylation of transcriptional factor STAT5B. The phosphorylation of STAT5B on the JAK2-dependent Y699 site is significantly reduced in the liver and skeletal muscles of Cry-deficient mice. At the same time, phosphorylation of JAK2 kinase was not reduced upon Cry deficiency, which places CRY activity downstream from JAK2. Thus CRYs link the circadian clock and JAK-STAT signaling through control of STAT5B phosphorylation, which provides the mechanism for circadian rhythms in IGF signaling in vivo.