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

Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. During mitosis, cyclin-dependent kinase 1 (CDK1) substitutes for mTOR and fully phosphorylates 4E-BP1 at canonica...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2016-07, Vol.113 (30), p.8466-8471
Main Authors: Velásquez, Celestino, Cheng, Erdong, Shuda, Masahiro, Lee-Oesterreich, Paula J., von Strandmann, Lisa Pogge, Gritsenko, Marina A., Jacobs, Jon M., Moore, Patrick S., Chang, Yuan
Format: Article
Language:English
Subjects:
4E-BP1, cyclin-dependent kinase 1, centrosome, mitosis
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - metabolism
Animals
Antigens
BASIC BIOLOGICAL SCIENCES
Biological Sciences
CDC2 Protein Kinase - genetics
CDC2 Protein Kinase - metabolism
Cell division
Cell Line
Cell Line, Tumor
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Centrosome - metabolism
Eukaryotes
HCT116 Cells
HEK293 Cells
HeLa Cells
Humans
Mitosis - genetics
Mutation
Phosphoproteins - genetics
Phosphoproteins - metabolism
Phosphorylation
Protein Biosynthesis
Proteins
RNA, Messenger - genetics
Rodents
Serine - genetics
Serine - metabolism
Tumors
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Summary:Mammalian target of rapamycin (mTOR)-directed eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) phosphorylation promotes cap-dependent translation and tumorigenesis. During mitosis, cyclin-dependent kinase 1 (CDK1) substitutes for mTOR and fully phosphorylates 4E-BP1 at canonical sites (T37, T46, S65, and T70) and the noncanonical S83 site, resulting in a mitosis-specific hyperphosphorylated δ 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. Although S83 phosphorylation of 4E-BP1 does not affect general cap-dependent translation, expression of an alanine substitution mutant 4E-BP1.S83A partially reverses rodent cell transformation induced by Merkel cell polyomavirus small T antigen viral oncoprotein. In contrast to inhibitory mTOR 4E-BP1 phosphorylation, these findings suggest that mitotic CDK1-directed phosphorylation of δ-4E-BP1 may yield a gain of function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1607768113