title: Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival.
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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors.forename: Yubao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215; Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Michael
authors.initials: M
authors.lastname: Begley
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors.forename: Hai-Tsang
authors.initials: HT
authors.lastname: Huang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors.forename: Ana
authors.initials: A
authors.lastname: Lako
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Eck
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA 02115;
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Mitchison
authors.affiliation: 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.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: 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.
authors.forename: Jean J
authors.initials: JJ
authors.lastname: Zhao
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D017124:Conserved Sequence; D039642:Eukaryotic Initiation Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008938:Mitosis; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics* / Q000378:metabolism; D019151:Peptide Library; D010766:Phosphorylation; D011485:Protein Binding; D014176:Protein Biosynthesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: D039642:Eukaryotic Initiation Factors; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019151:Peptide Library; D034741:RNA, Small Interfering; C031799:eIF-4B; C484610:MELK protein, human; D017346:Protein Serine-Threonine Kinases
keywords: MCL1; MELK; eIF4B; mitosis; protein synthesis