TY - JOUR
T1 - PKM2 Regulates Chromosome Segregation and Mitosis Progression of Tumor Cells
AU - Jiang, Yuhui
AU - Li, Xinjian
AU - Yang, Weiwei
AU - Hawke, David H.
AU - Zheng, Yanhua
AU - Xia, Yan
AU - Aldape, Kenneth
AU - Wei, Chongyang
AU - Guo, Fang
AU - Chen, Yan
AU - Lu, Zhimin
N1 - Funding Information:
We thank Don Cleveland (Ludwig Institute for Cancer Research, UCSD) for the LAP-CENP-T and CENP-U plasmids, Iain M. Cheeseman (Whitehead Institute for Biomedical Research, MIT) for the mCherry-H2B plasmid, and Katsumi Kitagawa (St. Jude Children’s Research Hospital) for His-Bub3 and Bub1 plasmids. We thank Lewis Cantley and Costas Lyssiotis for their insightful suggestions and Dawn Chalaire for her critical reading of this manuscript. This work was supported by National Cancer Institute grants 2R01CA109035 (Z.L.), 1R0CA169603 (Z.L.), and CA16672 (Cancer Center Support Grant); research grants (RP110252 and RP130389; Z.L.) from the Cancer Prevention and Research Institute of Texas (CPRIT); an American Cancer Society Research Scholar Award (RSG-09-277-01-CSM; Z.L.); the James S. McDonnell Foundation 21 st Century Science Initiative in Brain Cancer Research Award (220020318; Z.L.); and the Odyssey Fellowship from The University of Texas MD Anderson Cancer Center (Y.J.).
PY - 2014/1/9
Y1 - 2014/1/9
N2 - Tumor-specific pyruvate kinase M2 (PKM2) is instrumental in both aerobic glycolysis and gene transcription. PKM2 regulates G1-S phase transition by controlling cyclin D1 expression. However, it is not known whether PKM2 directly controls cell-cycle progression. We show here that PKM2, but not PKM1, binds to the spindle checkpoint protein Bub3 during mitosis and phosphorylates Bub3 at Y207. This phosphorylation is required for Bub3-Bub1 complex recruitment to kinetochores, where it interacts with Blinkin and is essential for correct kinetochore-microtubule attachment, mitotic/spindle-assembly checkpoint, accurate chromosome segregation, cell survival and proliferation, and active EGF receptor-induced brain tumorigenesis. In addition, the level of Bub3 Y207 phosphorylation correlated with histone H3-S10 phosphorylation in human glioblastoma specimens and with glioblastoma prognosis. These findings highlight the role of PKM2 as a protein kinase controlling the fidelity of chromosome segregation, cell-cycle progression, and tumorigenesis.
AB - Tumor-specific pyruvate kinase M2 (PKM2) is instrumental in both aerobic glycolysis and gene transcription. PKM2 regulates G1-S phase transition by controlling cyclin D1 expression. However, it is not known whether PKM2 directly controls cell-cycle progression. We show here that PKM2, but not PKM1, binds to the spindle checkpoint protein Bub3 during mitosis and phosphorylates Bub3 at Y207. This phosphorylation is required for Bub3-Bub1 complex recruitment to kinetochores, where it interacts with Blinkin and is essential for correct kinetochore-microtubule attachment, mitotic/spindle-assembly checkpoint, accurate chromosome segregation, cell survival and proliferation, and active EGF receptor-induced brain tumorigenesis. In addition, the level of Bub3 Y207 phosphorylation correlated with histone H3-S10 phosphorylation in human glioblastoma specimens and with glioblastoma prognosis. These findings highlight the role of PKM2 as a protein kinase controlling the fidelity of chromosome segregation, cell-cycle progression, and tumorigenesis.
UR - http://www.scopus.com/inward/record.url?scp=84892366115&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84892366115&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2013.11.001
DO - 10.1016/j.molcel.2013.11.001
M3 - Article
C2 - 24316223
AN - SCOPUS:84892366115
SN - 1097-2765
VL - 53
SP - 75
EP - 87
JO - Molecular cell
JF - Molecular cell
IS - 1
ER -