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

作者：Velasquez Celestino; Cheng Erdong; Shuda Masahiro; Lee Oesterreich Paula J; von Strandmann Lisa Pogge; Gritsenko Marina A; Jacobs Jon M; Moore Patrick S^*; Chang Yuan^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2016, 113(30): 8466-8471.

DOI：10.1073/pnas.1607768113

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

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 delta 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 delta-4E-BP1 may yield a gain of function, distinct from translation regulation, that may be important in tumorigenesis and mitotic centrosome function.

• 出版日期2016-7-26