PP2A-B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle-related genes
PP2A-B55 and its adapter proteins IER2 and IER5 regulate the activity of RB family proteins and the expression of cell cycle-related genes
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DOI：
10.1111/febs.16612
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发表时间：
2022-09-12
期刊：
影响因子：
5.4
通讯作者：
Sakurai, Hiroshi
中科院分区：
文献类型：
--
作者：
Doi, Kuriko;Takeuchi, Hiroto;Sakurai, Hiroshi
视网膜母细胞瘤（RB）肿瘤抑制蛋白调节细胞增殖、运动、分化和凋亡。RB的磷酸化状态由激酶和磷酸酶调节，RB与E2F家族转录因子表现出磷酸化敏感的相互作用。在这里，我们表征了蛋白磷酸酶2A （PP2A）对RB的去磷酸化作用。生长因子诱导的即时早期反应（IER）蛋白IER2和IER5具有适配器样功能，其中IER蛋白与PP2A及其靶蛋白结合并增强PP2A对蛋白质的活性。IER2与RB相互作用，促进PP2A对RB在T821/T826位点的去磷酸化。在IER2敲低的细胞中，RB磷酸化升高导致RB与启动子结合减少，cyclin D1和p21表达降低。IER5结合RB和RB样1 (p107/RBL1)，增强PP2A对这些蛋白的去磷酸化，抑制各种细胞周期相关基因的表达。然而，ier2调控的T821/T826的去磷酸化并不是RB抑制细胞移动性相关基因表达的必要条件。我们的数据确定PP2A适配器蛋白是RB家族蛋白的关键调节因子，并表明RB的磷酸化状态对基因表达有差异影响。
The retinoblastoma (RB) tumour suppressor protein regulates cell proliferation, motility, differentiation and apoptosis. The phosphorylation state of RB is modulated by kinases and phosphatases, and RB exhibits phosphorylation-sensitive interactions with E2F family transcription factors. Here, we characterize RB dephosphorylation by protein phosphatase 2A (PP2A). The growth factor-inducible immediate early response (IER) proteins IER2 and IER5 possess an adapter-like function in which IER proteins bind to both PP2A and its target proteins and enhance PP2A activity towards the proteins. IER2 interacts with RB and facilitates dephosphorylation of RB at T821/T826 by PP2A. In IER2 knockdown cells, elevated phosphorylation of RB resulted in reduced binding of RB to the promoters and derepression of cyclin D1 and p21. IER5 binds to both RB and RB-like 1 (p107/RBL1), enhances dephosphorylation of these proteins by PP2A and represses the expression of various cell cycle-related genes. However, IER2-regulated dephosphorylation at T821/T826 is not necessary for the repression function of RB in cell mobility-related gene expression. Our data identify PP2A adapter proteins as critical regulators of RB family proteins and suggest that the phosphorylation status of RB differentially affects gene expression.