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Published on: May 1, 2020
Mitotic MELK-eIF4B signaling controls protein synthesis and tumor cell survival
Yubao Wang1, Michael Begley2, Qing Li1
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115;
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.
Insights
Maternal and embryonic leucine zipper kinase (MELK) targets eukaryotic translation initiation factor 4B (eIF4B) to regulate protein synthesis during mitosis. This pathway controls myeloid cell leukemia 1 (MCL1) production, impacting cancer cell survival and apoptosis.
Area of Science:
- Molecular Biology
- Cancer Cell Biology
- Biochemistry
Background:
- Maternal and embryonic leucine zipper kinase (MELK) is crucial for cancer cell mitosis.
- The precise molecular mechanisms of MELK in cancer progression are not fully understood.
Purpose of the Study:
- To elucidate the role of MELK in mitotic progression and cancer cell survival.
- To identify MELK-interacting proteins and substrates involved in mitosis.
Main Methods:
- Immunoprecipitation followed by mass spectrometry (IP/MS) to identify MELK interactors.
- Peptide library profiling to determine MELK kinase activity and substrate specificity.
- Western blotting and apoptosis assays to validate findings.
Main Results:
- Identified eukaryotic translation initiation factor 4B (eIF4B) as a MELK-binding protein and substrate during mitosis.
- Demonstrated that MELK phosphorylates eIF4B at Ser406, a key event in mitosis.
- Established a MELK-eIF4B signaling axis that controls the synthesis of myeloid cell leukemia 1 (MCL1).
- Showed that inhibition of MELK or eIF4B reduces MCL1 synthesis, leading to cancer cell apoptosis.
Conclusions:
- Defined a novel MELK-eIF4B signaling pathway regulating protein synthesis during mitosis.
- This pathway is critical for the production of the antiapoptotic protein MCL1, influencing cancer cell survival.
- Targeting the MELK-eIF4B axis presents a potential therapeutic strategy for cancer treatment.
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