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CDK13 phosphorylates the translational machinery and promotes tumorigenic protein synthesis

ABSTRACT: Cyclin-dependent kinases 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. Herein, we identify key translation machinery components 4E-BP1 and eIF4B as novel CDK13 substrates. CDK13 directly phosphorylates 4E-BP1 at Thr46 and eIF4B at Ser422 such that genetic or pharmacological inhibition of CDK13 perturbs RNA translation. Polysome profiling analysis shows that MYC oncoprotein synthesis depends on the CDK13-regulated translation in colorectal cancer (CRC), and CDK13 is required for CRC cell proliferation. As mTORC1 has been shown to phosphorylate the 4E-BP1 and eIF4B, knockdown or inhibition of CDK13 in combination with mTORC1 inhibitor rapamycin further dephosphorylates 4E-BP1 and eIF4B and blocks protein synthesis. As a result, dual inhibition of CDK13 and mTORC1 accelerated CRC cell death and again MYC were significantly downregulated upon combination treatment. These findings demonstrate a pro-tumorigenic role of CDK13 in CRC and shed light on the role of CDK13 in protein synthesis by direct phosphorylation of translation initiation factors. Therefore, therapeutic targeting of CDK13 alone or in combination with rapamycin may pave a new way for CRC treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224287 | GEO | 2023/03/09

REPOSITORIES: GEO

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