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首页> 外文期刊>Molecular and Cellular Biology >BRF1 Protein Turnover and mRNA Decay Activity Are Regulated by Protein Kinase B at the Same Phosphorylation Sites
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BRF1 Protein Turnover and mRNA Decay Activity Are Regulated by Protein Kinase B at the Same Phosphorylation Sites

机译：BRF1蛋白质周转率和mRNA衰变活性是由蛋白质激酶B在相同的磷酸化位点调节的。

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BRF1 posttranscriptionally regulates mRNA levels by targeting ARE-bearing transcripts to the decay machinery. We previously showed that protein kinase B (PKB) phosphorylates BRF1 at Ser92, resulting in binding to 14-3-3 and impairment of mRNA decay activity. Here we identify an additional regulatory site at Ser203 that cooperates in vivo with Ser92. In vitro kinase labeling and wortmannin sensitivity indicate that Ser203 phosphorylation is also performed by PKB. Mutation of both serines to alanine uncouples BRF1 from PKB regulation, leading to constitutive mRNA decay even in the presence of stabilizing signals. BRF1 protein is labile because of proteasomal degradation (half-life, <3 h) but becomes stabilized upon phosphorylation and is less stable in PKBα?/? cells. Surprisingly, phosphorylation-dependent protein stability is also regulated by Ser92 and Ser203, with parallel phosphorylation required at these sites. Phosphorylation-dependent binding to 14-3-3 is abolished only when both sites are mutated. Cell compartment fractionation experiments support a model in which binding to 14-3-3 sequesters BRF1 through relocalization and prevents it from executing its mRNA decay activity, as well as from proteasomal degradation, thereby maintaining high BRF1 protein levels that are required to reinstate decay upon dissipation of the stabilizing signal.
机译：BRF1通过将带有ARE的转录物靶向衰变机制来转录后调节mRNA水平。我们以前显示蛋白激酶B（PKB）使Ser92处的BRF1磷酸化，导致与14-3-3的结合以及mRNA衰变活性的降低。在这里，我们确定了Ser203上与Ser92在体内协同作用的其他调控位点。体外激酶标记和渥曼青霉素敏感性表明，Ser203磷酸化也由PKB进行。两种丝氨酸向丙氨酸的突变使BRF1与PKB调节脱钩，即使存在稳定信号也导致组成型mRNA衰减。 BRF1蛋白由于蛋白酶体降解（半衰期，<3小时）而不稳定，但在磷酸化后变得稳定，并且在PKBα？/？细胞中不稳定。出人意料的是，磷酸化依赖性蛋白的稳定性也受Ser92和Ser203的调节，在这些位点需要平行的磷酸化。仅当两个位点都突变时，才取消与14-3-3的磷酸化依赖性结合。细胞室分离实验支持一种模型，该模型通过重新定位与14-3-3螯合剂BRF1结合，阻止其执行其mRNA衰变活性以及蛋白酶体降解，从而维持在恢复时恢复衰变所需的高BRF1蛋白水平。稳定信号的耗散。

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