Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism.
Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism.
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DOI：
10.1016/j.molcel.2011.10.015
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发表时间：
2011-12-23
期刊：
影响因子：
16
通讯作者：
Chen, Jing
中科院分区：
文献类型：
--
作者：
Hitosugi, Taro;Fan, Jun;Chung, Tae-Wook;Lythgoe, Katherine;Wang, Xu;Xie, Jianxin;Ge, Qingyuan;Gu, Ting-Lei;Polakiewicz, Roberto D.;Roesel, Johannes L.;Chen, Georgia Z.;Boggon, Titus J.;Lonial, Sagar;Fu, Haian;Khuri, Fadlo R.;Kang, Sumin;Chen, Jing
许多肿瘤细胞依靠有氧糖酵解而不是氧化磷酸化来持续增殖和存活。Myc和HIF-1被认为部分地通过上调丙酮酸脱氢酶（PDH）激酶1（PDHK 1）的基因表达来促进这种代谢转换，所述丙酮酸脱氢酶激酶1使线粒体PDH磷酸化并失活，并因此使丙酮酸脱氢酶复合物（PDC）失活。在这里，我们报告，酪氨酸磷酸化增强PDHK 1激酶活性，促进ATP和PDC的结合。功能性PDC可以在一些癌细胞基质外的线粒体中形成，并且PDHK 1在人类癌症中通常被定位于不同线粒体区室的多种致癌酪氨酸激酶酪氨酸磷酸化。在癌细胞中表达磷酸化缺陷型、催化性亚型PDHK 1突变体导致缺氧条件下细胞增殖减少，氧化磷酸化增加，线粒体丙酮酸利用增强，异种移植裸鼠肿瘤生长减少。同时，酪氨酸磷酸化激活PDHK 1以促进瓦尔堡效应和肿瘤生长。
Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for their continued proliferation and survival. Myc and HIF-1 are believed to promote such a metabolic switch by, in part, upregulating gene expression of pyruvate dehydrogenase (PDH) kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial PDH and consequently pyruvate dehydrogenase complex (PDC). Here we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of matrix in some cancer cells and PDHK1 is commonly tyrosine phosphorylated in human cancers by diverse oncogenic tyrosine kinases localized to different mitochondrial compartments. Expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate, and reduced tumor growth in xenograft nude mice. Together, tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth.
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影响因子：
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