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首页> 外文期刊>Cellular Signalling >Phosphorylation dynamics of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) is discordant with its potential to interact with eukaryotic initiation factor 4E (eIF4E)
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Phosphorylation dynamics of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) is discordant with its potential to interact with eukaryotic initiation factor 4E (eIF4E)

机译：真核生物起始因子4E结合蛋白1（4E-BP1）的磷酸化动力学与其与真核生物起始因子4E（eIF4E）相互作用的潜力不一致

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摘要

Mammalian target of rapamycin (mTOR) controls cellular growth and proliferation by virtue of its ability to regulate protein translation. Eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4E-BP1) -- a key mTOR substrate, binds and sequesters eIF4E to impede translation initiation that is supposedly overcome upon 4E-BP1 phosphorylation by mTOR. Ambiguity surrounding the precise identity of mTOR regulated sites in 4E-BP1 and their invariable resistance to mTOR inactivation raises concerns about phospho-regulated model proposed for 4E:4E-BP1 interaction. Our attempt to mimic dephosphorylation associated with rapamycin response by introducing phospho deficient mutants for sites implicated in regulating 4E:4E-BP1 interaction individually or globally highlighted no obvious difference in the quantum of their association with CAP bound 4E when compared with their phosphomimicked counterparts or the wild type 4E-BP1. TOS or RAIP motif deletion variants compromised for raptor binding and resultant phosphodeficiency did little to influence their association with CAP bound 4E. Interestingly ectopic expression of ribosomal protein S6 kinase 1 (S6K1) that restored 4E-BP1 sensitivity to rapamycin/Torin reflected by instant loss of 4E-BP1 phosphorylation, failed to bring about any obvious change in 4E:4E-BP1 stoichiometry. Our data clearly demonstrate a potential disconnect between rapamycin response of 4E-BP1 and its association with CAP bound 4E.
机译：雷帕霉素（mTOR）的哺乳动物靶标凭借其调节蛋白质翻译的能力来控制细胞的生长和增殖。真核起始因子4E（eIF4E）结合蛋白1（4E-BP1）-一个关键的mTOR底物，结合并隔离eIF4E来阻止翻译起始，据认为在mE的4E-BP1磷酸化后可以克服。围绕4E-BP1中mTOR调控位点的精确身份及其对mTOR失活的不变抗性的歧义引起了人们对为4E：4E-BP1相互作用提出的磷酸调控模型的担忧。我们尝试通过引入磷酸缺乏突变体来模拟与雷帕霉素反应相关的去磷酸化，该突变体涉及单独或全局调控4E：4E-BP1相互作用的位点，与它们的磷酸化类似物相比，与CAP结合的4E缔合的结合量没有明显差异。野生型4E-BP1。猛禽结合受损的TOS或RAIP基序缺失变体，导致的磷酸缺乏对影响它们与CAP结合的4E的关联影响很小。有趣的是，异位表达的核糖体蛋白S6激酶1（S6K1）恢复了4E-BP1对雷帕霉素/ Torin的敏感性，反映为4E-BP1磷酸化的瞬时丧失，未能引起4E：4E-BP1化学计量的任何明显变化。我们的数据清楚地表明，雷帕霉素对4E-BP1的应答与其与CAP结合的4E的关联之间存在潜在的脱节。

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