Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation.
Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation.
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DOI：
10.1038/nature10598
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发表时间：
2011-12-01
期刊：
影响因子：
64.8
通讯作者：
Lu, Zhimin
中科院分区：
文献类型：
--
作者：
Yang, Weiwei;Xia, Yan;Ji, Haitao;Zheng, Yanhua;Liang, Ji;Huang, Wenhua;Gao, Xiang;Aldape, Kenneth;Lu, Zhimin
胚胎丙酮酸激酶M2(PKM2)亚型在人类肿瘤中高表达。与PKM2在有氧糖酵解或Warburg效应中的既定作用相反，它的非代谢功能仍然难以捉摸。在这里，我们证明了EGFR的激活诱导了PKM2的移位，而不是PKM1的移位，在那里PKM2的K433与β-连环蛋白的c-Src磷酸化的Y333结合。这种相互作用是两种蛋白质被招募到CCND1启动子上所必需的，导致HDAC3从启动子上移除，组蛋白H3乙酰化，以及细胞周期蛋白D1的表达。依赖于PKM2的β-连环蛋白的反式激活在EGFR促进的肿瘤细胞增殖和脑肿瘤的发生中起重要作用。此外，在人脑胶质母细胞瘤标本中，c-src活性、β-catenin Y333磷酸化和PKM2核积聚之间也存在正相关关系。此外，β-连环蛋白磷酸化水平和核PKM2水平与胶质瘤的恶性程度和预后相关。这些发现揭示了表皮生长因子通过与Wnt/Wingless不同的机制诱导β-catenin反式激活，并强调了PKM2在EGFR促进的β-catenin反式激活、细胞增殖和肿瘤发生中的必要的非代谢功能。
The embryonic pyruvate kinase M2 (PKM2) isoform is highly expressed in human cancer. In contrast to the established role of PKM2 in aerobic glycolysis or the Warburg effect, its nonmetabolic functions remain elusive. Here we demonstrate that EGFR activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of β-catenin. This interaction is required for both proteins to be recruited to the CCND1 promoter, leading to HDAC3 removal from the promoter, histone H3 acetylation, and cyclin D1 expression. PKM2-dependent β-catenin transactivation is instrumental in EGFR-promoted tumor cell proliferation and brain tumor development. In addition, positive correlations have been identified among c-Src activity, β-catenin Y333 phosphorylation, and PKM2 nuclear accumulation in human glioblastoma specimens. Furthermore, levels of β-catenin phosphorylation and nuclear PKM2 have been correlated with grades of glioma malignancy and prognosis. These findings reveal that EGF induces β-catenin transactivation via a mechanism distinct from that induced by Wnt/wingless and highlight the essential nonmetabolic functions of PKM2 in EGFR-promoted β-catenin transactivation, cell proliferation, and tumorigenesis.
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影响因子：
5.7
作者：
Petalidis LP;Oulas A;Backlund M;Wayland MT;Liu L;Plant K;Happerfield L;Freeman TC;Poirazi P;Collins VP
通讯作者：
Collins VP
影响因子：
50.3
作者：
Phillips, HS;Kharbanda, S;Aldape, K
通讯作者：
Aldape, K
DOI：
10.1073/pnas.0611576104
发表时间：
2007-02-27
影响因子：
11.1
作者：
Yochum, Gregory S.;McWeeney, Shannon;Goodman, Richard H.
通讯作者：
Goodman, Richard H.
DOI：
10.1016/s0065-2571(01)00036-x
发表时间：
2002-01-01
期刊：
ADVANCES IN ENZYME REGULATION, VOL 42, PROCEEDINGS
影响因子：
--
作者：
Le Mellay, V;Houben, R;Rapp, UR
通讯作者：
Rapp, UR
影响因子：
16
作者：
Xia, Yan;Wang, Ji;Lu, Zhimin
通讯作者：
Lu, Zhimin