Mitotic Protein Kinase CDK1 Phosphorylation of mRNA Translation Regulator 4E-BP1 Ser83 May Contribute to Cell Transformation

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • CDC2 Protein Kinase / genetics
  • CDC2 Protein Kinase / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Centrosome / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Mitosis / genetics
  • Mutation
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Biosynthesis
  • RNA, Messenger / genetics
  • Serine / genetics
  • Serine / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • EIF4EBP1 protein, human
  • Phosphoproteins
  • RNA, Messenger
  • Serine
  • CDC2 Protein Kinase
  • CDK1 protein, human