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Proc Natl Acad Sci U S A. 2016 Aug 30;113(35):9810-5. doi: 10.1073/pnas.1606862113. Epub 2016 Aug 15.

Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
2
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
3
Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
4
Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; Department of Systems Biology, Harvard Medical School, Boston, MA 02115; Meyer Cancer Center, Department of Medicine, Weill Cornell Medical College, New York, NY 10065 cantley@med.cornell.edu jean_zhao@dfci.harvard.edu.
5
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; cantley@med.cornell.edu jean_zhao@dfci.harvard.edu.

Abstract

The protein kinase maternal and embryonic leucine zipper kinase (MELK) is critical for mitotic progression of cancer cells; however, its mechanisms of action remain largely unknown. By combined approaches of immunoprecipitation/mass spectrometry and peptide library profiling, we identified the eukaryotic translation initiation factor 4B (eIF4B) as a MELK-interacting protein during mitosis and a bona fide substrate of MELK. MELK phosphorylates eIF4B at Ser406, a modification found to be most robust in the mitotic phase of the cell cycle. We further show that the MELK-eIF4B signaling axis regulates protein synthesis during mitosis. Specifically, synthesis of myeloid cell leukemia 1 (MCL1), an antiapoptotic protein known to play a role in cancer cell survival during cell division, depends on the function of MELK-elF4B. Inactivation of MELK or eIF4B results in reduced protein synthesis of MCL1, which, in turn, induces apoptotic cell death of cancer cells. Our study thus defines a MELK-eIF4B signaling axis that regulates protein synthesis during mitosis, and consequently influences cancer cell survival.

KEYWORDS:

MCL1; MELK; eIF4B; mitosis; protein synthesis

PMID:
27528663
PMCID:
PMC5024598
[Available on 2017-02-28]
DOI:
10.1073/pnas.1606862113
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

L.C.C. is a member of the Board of Directors of, and holds equity in Agios Pharmaceuticals, a company that is developing drugs that target cancer metabolism. L.C.C. is also a founder of and holds equity in Petra Pharmaceuticals. The data presented in this manuscript are unrelated to research at Agios Pharmaceuticals or Petra Pharmaceuticals. The phosphorylation of eIF4B and related methods of use reported in this study are covered in the following published patent application: WO 2015073509 A2.

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