Cyclin-dependent kinase 13 (CDK13) has been suggested to phosphorylate RNA polymerase II and is involved in transcriptional activation. However, whether CDK13 catalyzes other protein substrates and how CDK13 contributes to tumorigenesis remain largely unclear. We here identify key translation machinery components, 4E-BP1 and eIF4B, as novel CDK13 substrates. CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422; genetically or pharmacologically inhibiting CDK13 disrupts mRNA translation. Polysome profiling analysis shows that MYC oncoprotein synthesis strictly depends on CDK13-regulated translation in colorectal cancer (CRC), and CDK13 is required for CRC cell proliferation. As mTORC1 is implicated in 4E-BP1 and eIF4B phosphorylation, inactivation of CDK13 in combination with the mTORC1 inhibitor rapamycin further dephosphorylates 4E-BP1 and eIF4B and blocks protein synthesis. As a result, dual inhibition of CDK13 and mTORC1 induces more profound tumor cell death. These findings clarify the pro-tumorigenic role of CDK13 by direct phosphorylation of translation initiation factors and enhancing protein synthesis. Therefore, therapeutic targeting of CDK13 alone or in combination with rapamycin may pave a new way for cancer treatment.

细胞周期蛋白依赖性激酶 13 (CDK13) 已被建议磷酸化 RNA 聚合酶 II，并参与转录激活。然而，CDK13 是否催化其他蛋白质底物以及 CDK13 如何促进肿瘤发生在很大程度上仍不清楚。我们在此将关键翻译机器组件 4E-BP1 和 eIF4B 确定为新型 CDK13 底物。CDK13 直接磷酸化 Thr46 位点的 4E-BP1 和 Ser422 位点的 eIF4B；遗传或药理学抑制 CDK13 会破坏 mRNA 翻译。多核糖体分析表明，MYC 癌蛋白的合成严格依赖于结直肠癌 (CRC) 中 CDK13 调节的翻译，而 CDK13 是 CRC 细胞增殖所必需的。由于 mTORC1 与 4E-BP1 和 eIF4B 磷酸化有关，CDK13 的失活与 mTORC1 抑制剂雷帕霉素联合使用可进一步使 4E-BP1 和 eIF4B 去磷酸化并阻断蛋白质合成。因此，CDK13 和 mTORC1 的双重抑制会诱导更严重的肿瘤细胞死亡。这些发现通过翻译起始因子的直接磷酸化和增强蛋白质合成阐明了 CDK13 的促肿瘤发生作用。因此，单独靶向CDK13或与雷帕霉素联合治疗可能为癌症治疗开辟一条新途径。