PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect
PKM2 Tyrosine Phosphorylation and Glutamine Metabolism Signal a Different View of the Warburg Effect
复制标题
DOI：
10.1126/scisignal.297pe75
复制
发表时间：
2009-11-17
影响因子：
7.3
通讯作者：
Dang, Chi V.
中科院分区：
文献类型：
--
作者：
Dang, Chi V.
新的证据表明，受体酪氨酸激酶FGFR 1（成纤维细胞生长因子受体1）直接磷酸化丙酮酸激酶M2（PKM 2），导致磷酸烯醇丙酮酸转化为丙酮酸的转化减少，丙酮酸进一步被乳酸脱氢酶A分解代谢为乳酸。关键酪氨酸Tyr（105）突变为Phe使PKM2更活跃，但与野生型PKM2相比，细胞乳酸产生减少，耗氧量增加，缺氧细胞增殖减少相关。通过酪氨酸磷酸化的生长信号传导的明显矛盾效应，其降低而不是增加PKM 2活性，刺激了对瓦尔堡效应的修正观点。这种效应描述了癌细胞以高速率将葡萄糖转化为乳酸的倾向，现在必须适应癌细胞中糖酵解、三羧酸循环和谷氨酰胺代谢之间的联系。
New evidence suggests that the receptor tyrosine kinase FGFR1 (fibroblast growth factor receptor 1) directly phosphorylates pyruvate kinase M2 (PKM2), resulting in reduced conversion of phosphoenolpyruvate to pyruvate, which is further catabolized to lactate by lactate dehydrogenase A. Mutation of the critical tyrosine Tyr(105) to Phe rendered PKM2 more active but was associated with decreased cellular lactate production, increased oxygen consumption, and decreased hypoxic cell proliferation relative to wild-type PKM2. The apparent paradoxical effect of growth signaling through tyrosine phosphorylation, which decreases rather than increases PKM2 activity, stimulates a revised perspective of the Warburg effect. This effect, which describes the propensity for cancer cells to convert glucose to lactate at a high rate, must now accommodate links among glycolysis, the tricarboxylic acid cycle, and glutamine metabolism in cancer cells.