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Regulation of the stability and activity of CDC25A and CDC25B by protein phosphatase PP2A and 14-3-3 binding

机译:用蛋白质磷酸酶PP2A和14-3-3结合调节CDC25A和CDC25B的稳定性和活性

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Cyclin-dependent kinase (CDK)-activating phosphatases, CDC25A and CDC25B, are labile proteins, and their levels vary in a cell cycle-dependent manner. Immediate-early response IER5 protein negatively regulates the cellular CDC25B levels, and stress-induced IER5 expression potentiates G2/M arrest. IER5 binds to protein phosphatase PP2A and regulates the PP2A substrate specificity. We show that IER5 binds to CDC25B and assists PP2A to convert CDC25B to hypophosphorylated forms. Hypophosphorylation at Ser323 results in the dissociation of CDC25B from 14-3-3 phospho-binding proteins. In IER5 expressing cells, CDC25B dissociated from 14-3-3 is unstable but slightly activated, because 14-3-3 inhibits CDC25B polyubiquitination and CDC25B binding to CDK1. The 14-3-3 binding to CDC25A also impedes CDC25A degradation and CDC25A-CDK2 interaction. We propose that 14-3-3 is an important regulator of CDC25A and CDC25B and that PP2A/IER5 controls the stability and activity of CDC25B through regulating the interaction of CDC25B and 14-3-3.
机译:细胞周期蛋白依赖性激酶(CDK) - 活化的磷​​酸酶,CDC25A和CDC25B是不稳定的蛋白质,它们的水平以细胞周期依赖性方式变化。立即早期的反应IER5蛋白负调节细胞CDC25B水平,并应激诱导的IER5表达增强剂G2 / M被捕。 IER5与蛋白质磷酸酶PP2A结合并调节PP2A底物特异性。我们表明IER5绑定到CDC25B,并有助于PP2A将CDC25B转换为低磷酸化形式。 SER323的次磷酸化导致CDC25B的解离14-3-3磷酸蛋白结合蛋白。在IER5表达细胞中,CDC25b离解离14-3-3的CDC25b是不稳定但略微活化的,因为14-3-3抑制CDC25B的络合和CDC25B结合CDK1。 14-3-3与CDC25a结合也阻抗CDC25A降解和CDC25A-CDK2相互作用。我们提出14-3-3是CDC25A和CDC25B的重要调节剂,并且PP2A / IER5通过调节CDC25B和14-3-3的相互作用来控制CDC25B的稳定性和活性。

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