Rapamycin-insensitive mTORC1 activity controls eIF4E:4E-BP1 binding.
Rapamycin-insensitive mTORC1 activity controls eIF4E:4E-BP1 binding.
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DOI：
10.12688/f1000research.1-4.v1
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Bidinosti M
中科院分区：
文献类型：
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作者：
Livingstone M;Bidinosti M
最近开发的哺乳动物雷帕霉素靶点 (mTOR) 激酶结构域抑制剂以及对雷帕霉素敏感和不敏感的 mTOR 蛋白复合物（mTORC1 和 mTORC2）的基因剖析揭示了 mTOR 底物 4E-BP1 在氨基酸 Thr37 和/或 Thr46 上的磷酸化代表了 mTORC1 的雷帕霉素不敏感活性。尽管之前有许多报道利用 4E-BP1 的丝氨酸 (Ser) 至丙氨酸 (Ala) 和苏氨酸 (Thr) 至 Ala 磷酸化位点突变体来评估哪些翻译后修饰直接调节与 eIF4E 的结合，但仍然存在模糊的理解。该手稿表明，Thr46 处的初始雷帕霉素不敏感磷酸化事件足以阻止 eIF4E:4E-BP1 结合。这一发现具有相关性，特别是在继续评估 mTOR 激酶结构域抑制剂的临床疗效的情况下，因为它阐明了这些第二代 mTOR 抑制剂与雷帕霉素类似物的作用之间的差异。
The recent development of mammalian target of rapamycin (mTOR) kinase domain inhibitors and genetic dissection of rapamycin-sensitive and -insensitive mTOR protein complexes (mTORC1 and mTORC2) have revealed that phosphorylation of the mTOR substrate 4E-BP1 on amino acids Thr37 and/or Thr46 represents a rapamycin-insensitive activity of mTORC1. Despite numerous previous reports utilizing serine (Ser)-to-alanine (Ala) and threonine (Thr)-to-Ala phosphorylation site mutants of 4E-BP1 to assess which post-translational modification(s) directly regulate binding to eIF4E, an ambiguous understanding persists. This manuscript demonstrates that the initial, rapamycin-insensitive phosphorylation event at Thr46 is sufficient to prevent eIF4E:4E-BP1 binding. This finding is relevant, particularly as mTOR kinase domain inhibitors continue to be assessed for clinical efficacy, since it clarifies a difference between the action of these second-generation mTOR inhibitors and those of rapamycin analogues.