期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 4, 页码 3033-3046出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.165340
关键词
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资金
- National Institutes of Health [DK-56292, CA132389]
- Clinical and Translational Science Award Program [UL1 RR025008]
- NCRR [G12RR03034]
- Chinese Natural Science Foundation [30500183, 30870990, 90508002, 90913016]
- Chinese Academy of Science [KSCX1-YW-R-65, KSCX2-YW-H-10, KSCX2-YW-R-195]
- Chinese 973 Project [2006CB943603, 2007CB914503, 2010CB912103]
- International Collaboration [2009DFA31010]
- Technology Grant [2006BAI08B01-07]
- China National Key Projects for Infectious Disease [2008ZX10002-021]
- Georgia Cancer Coalition breast cancer research
- Atlanta Clinical and Translational Science Award Chemical Biology [P20RR011104]
- Anhui Province Key Project [08040102005]
During cell division, interaction between kinetochores and dynamic spindle microtubules governs chromosome movements. The microtubule depolymerase mitotic centromere-associated kinesin (MCAK) is a key regulator of mitotic spindle assembly and dynamics. However, the regulatory mechanisms underlying its depolymerase activity during the cell cycle remain elusive. Here, we showed that PLK1 is a novel regulator of MCAK in mammalian cells. MCAK interacts with PLK1 in vitro and in vivo. The neck and motor domain of MCAK associates with the kinase domain of PLK1. MCAK is a novel substrate of PLK1, and the phosphorylation stimulates its microtubule depolymerization activity of MCAK in vivo. Overexpression of a polo-like kinase 1 phosphomimetic mutant MCAK causes a dramatic increase in misaligned chromosomes and in multipolar spindles in mitotic cells, whereas overexpression of a nonphosphorylatable MCAK mutant results in aberrant anaphase with sister chromatid bridges, suggesting that precise regulation of the MCAK activity by PLK1 phosphorylation is critical for proper microtubule dynamics and essential for the faithful chromosome segregation. We reasoned that dynamic regulation of MCAK phosphorylation by PLK1 is required to orchestrate faithful cell division, whereas the high levels of PLK1 and MCAK activities seen in cancer cells may account for a mechanism underlying the pathogenesis of genomic instability.
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