已知RNA结合蛋白Rbm38结合翻译起始因子eIF4E，GSK3β介导其S195磷酸化，进而阻断eIF4E结合，调控蛋白翻译。Rbm38缺失导致细胞和机体衰老。申请人发现Rbm38结合eIF4E2(eIF4E同源蛋白并响应缺氧)。有趣的是敲降eIF4E2抑制S195磷酸化。我们证明eIF4E2结合并调控GSK3β蛋白激酶活性。我们推测缺氧通过eIF4E2/GSK3β信号通路并依赖于Rbm38磷酸化调控细胞衰老。我们将鉴定eIF4E2介导缺氧信号转导的关键位点及其蛋白翻译后修饰。验证归纳eIF4E2调控GSK3β激酶活性的普遍规律。并结合翻译组学等方法研究eIF4E2/GSK3β信号通路依赖于Rbm38磷酸化调控蛋白翻译的机制。最后，以S193A点突变小鼠模型和突变细胞系为基础，结合异种移植等方法揭示eIF4E2/GSK3β信号通路依赖于Rbm38磷酸化调控细胞衰老，进而影响癌症发生的机制。

The RNA binding protein Rbm38 is known to bind to the translation initiation factor eIF4E. GSK3β mediates its phosphorylation of S195, which in turn blocks eIF4E binding and regulates protein translation. Deletion of Rbm38 promotes cell senescence and aging. Applicants have recently discovered that Rbm38 binds to eIF4E2 (eIF4E homologous protein, responds to hypoxia). Interestingly, knockdown of eIF4E2 inhibits S195 phosphorylation. We demonstrate that eIF4E2 directly binds to GSK3β and regulates its kinase activity. We speculate that hypoxia regulates cell senescence through the eIF4E2/GSK3β signaling pathway depends on Rbm38 S195 phosphorylation. We will identify the key sites and its post-translational modifications of eIF4E2, which mediated hypoxia signaling. We will validate the general rule that eIF4E2 controls the activity of GSK3β protein kinase. Meanwhile, combining Ribo-seq and other methods to reveal how the eIF4E2/GSK3 signaling pathway dependents on Rbm38 phosphorylation to regulate protein translation. Finally, based on the S193A point mutation mouse model and mutant cell lines, combined with xenograft and other methods to explore how the eIF4E2/GSK3β signaling pathway depends on Rbm38 phosphorylation to regulate cell senescence, thereby affecting the tumorigenesis.