July 22, 2020
Journal Article

Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation

Jon Jacobs
Marina Gritsenko
Erdong Cheng
Paula Lee-Oesterreich
Masahiro Shuda
Lisa Pogge von Strandmann
Yuan Chang
Patrick Moore
Celestino Velasquez

Abstract

mTOR-directed 4E-BP1 phosphorylation promotes cap-dependent translation and tumorigen-esis. During mitosis, CDK1 substitutes for mTOR and fully phosphorylates 4E-BP1 at canoni-cal as well a non-canonical S83 site resulting in a mitosis-specific hyperphosphorylated d isoform. Colocalization studies with a phospho-S83 specific antibody indicate that 4E-BP1 S83 phosphorylation accumulates at centrosomes during prophase, peaks at metaphase, and decreases through telophase. While S83 phosphorylation of 4E-BP1 does not affect in vitro cap-dependent translation, nor eIF4G/4E-BP1 cap-binding, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus (MCV) small T (sT) antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of d-4E-BP1 may yield a gain-of-function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.

Revised: July 22, 2020 | Published: July 26, 2016

Citation

Velasquez C., E. Cheng, M. Shuda, P.J. Lee-Oesterreich, L. Pogge von Strandmann, M.A. Gritsenko, and J.M. Jacobs, et al. 2016. "Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation." Proceedings of the National Academy of Sciences of the United States of America vol. 113, no. 30:8466-8471. PNNL-SA-116951. doi:10.1073/pnas.1607768113