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

TitleMitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival.
Publication TypeJournal Article
Year of Publication2016
AuthorsWang Y, Begley M, Li Q, Huang H-T, Lako A, Eck MJ, Gray NS, Mitchison TJ, Cantley LC, Zhao JJ
JournalProc Natl Acad Sci U S A
Date Published2016 Aug 30

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.

Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27528663
PubMed Central IDPMC5024598
Grant ListP50 CA168504 / CA / NCI NIH HHS / United States
R01 CA172461 / CA / NCI NIH HHS / United States
R01 GM039565 / GM / NIGMS NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States

Weill Cornell Medicine
Cantley Lab
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