CDK13 phosphorylates the translation machinery and promotes tumorigenic protein synthesis

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.

Automated summary

CDK13 can phosphorylate RNA polymerase II and other protein substrates, with unclear role in tumorigenesis. The study identifies 4E-BP1 and eIF4B as novel CDK13 substrates and shows that CDK13 regulates mRNA translation and MYC oncoprotein synthesis in colorectal cancer. Inactivation of CDK13 and mTORC1 inhibition leads to decreased protein synthesis and increased tumor cell death, suggesting therapeutic potential of targeting CDK13 alone or in combination with rapamycin for cancer treatment.