SKAR is a specific target of S6 kinase 1 in cell growth control
SKAR is a specific target of S6 kinase 1 in cell growth control
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DOI：
10.1016/j.cub.2004.08.061
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发表时间：
2004-09-07
期刊：
影响因子：
9.2
通讯作者：
Blenis, J
中科院分区：
文献类型：
--
作者：
Richardson, CJ;Bröenstrup, M;Blenis, J
背景：哺乳动物雷帕霉素靶点 (mTOR) 和磷脂酰肌醇 3-激酶 (PI3K) 信号通路可响应营养、能量和有丝分裂信号而促进细胞生长和细胞周期进程。在哺乳动物细胞中，核糖体蛋白 S6 激酶 S6K1 和 S6K2 位于 mTOR 和 PI3K 的下游，表明通过 S6 磷酸化的翻译控制可调节细胞生长。有趣的是，基因实验预测，S6K1 特异的底物（而非 S6K2）可调节细胞生长。结果：在这里，我们将 SKAR 确定为 S6K1（而非 S6K2）的新型特异性结合伴侣和底物。我们发现人 SKAR 的丝氨酸 383 和 385 是胰岛素刺激和雷帕霉素敏感的 S6K1 磷酸化位点。定量质谱分析表明，丝氨酸 383/385 磷酸化对 RNA 干扰 (RNAi) 介导的 S6K1 还原敏感，但对 S6K2 还原不敏感。此外，RNAi 介导的 SKAR 减少会减小细胞大小。 SKAR 是与 RNA 结合蛋白 Aly/REF 家族同源的核蛋白，已被提出将转录与前 mRNA 剪接和 mRNA 输出耦合。结论：我们已经确定了 S6K1 的一个新的特异性靶标 SKAR，它可调节细胞生长。 SKAR 与 Aly/REF 家族的同源性将 S6K1 与控制细胞生长的 mRNA 生物发生联系起来。
Background: The mammalian target of rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K) signaling pathways promote cell growth and cell cycle progression in response to nutritional, energy, and mitogenic cues. In mammalian cells, the ribosomal protein S6 kinases, S6K1 and S6K2, lie downstream of mTOR and PI3K, suggesting that translational control through the phosphorylation of S6 regulates cell growth. Interestingly, genetic experiments predict that a substrate that is specific to S6K1 but not S6K2 regulates cell growth.Results: Here we identify SKAR as a novel and specific binding partner and substrate of S6K1 but not S6K2. We find that serines 383 and 385 of human SKAR are insulin-stimulated and rapamycin-sensitive S6K1 phosphorylation sites. Quantitative mass spectrometry reveals that serine 383/385 phosphorylation is sensitive to RNA interference (RNAi)-mediated S6K1 reduction, but not S6K2 reduction. Furthermore, RNAi-mediated reduction of SKAR decreases cell size. SKAR is nuclear protein with homology to the Aly/REF family of RNA binding proteins, which has been proposed to couple transcription with pre-mRNA splicing and mRNA export.Conclusions: We have identified a novel and specific target of S6K1, SKAR, which regulates cell growth. The homology of SKAR to the Aly/REF family links S6K1 with mRNA biogenesis in the control of cell growth.