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Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):8466-71. doi: 10.1073/pnas.1607768113. Epub 2016 Jul 11.

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

Author information

1
Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213;
2
Biological Sciences Division/Biological Systems Analysis & Mass Spectrometry, Pacific Northwest National Laboratory, Richland, WA 99352.
3
Cancer Virology Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213; yc70@pitt.edu psm9@pitt.edu.

Abstract

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.

KEYWORDS:

4E-BP; Merkel cell polyomavirus; cap-dependent translation; cyclin-dependent kinase 1; mitosis

PMID:
27402756
PMCID:
PMC4968757
DOI:
10.1073/pnas.1607768113
[Indexed for MEDLINE]
Free PMC Article

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