Pyruvate kinase M2 is a phosphotyrosine-binding protein
Pyruvate kinase M2 is a phosphotyrosine-binding protein
复制标题
DOI：
10.1038/nature06667
复制
发表时间：
2008-03-13
期刊：
影响因子：
64.8
通讯作者：
Cantley, Lewis C.
中科院分区：
文献类型：
--
作者：
Christofk, Heather R.;Vander Heiden, Matthew G.;Cantley, Lewis C.
生长因子刺激细胞吸收多余的营养物质并将其用于合成代谢过程。这一过程的生化机制尚未完全了解，但它是由酪氨酸残基上的信号蛋白磷酸化引发的。使用一种新的磷酸酪氨酸结合蛋白的蛋白质组学筛选，我们观察到参与糖酵解的酶，人M2（胎儿）丙酮酸激酶（PKM 2）亚型，直接和选择性地结合酪氨酸磷酸化肽。我们表明，磷酸酪氨酸肽结合PKM 2的释放的变构激活剂果糖-1，6-二磷酸，导致抑制PKM 2酶活性的结果。我们还提供了证据表明，当细胞受到某些生长因子的刺激时，磷酸酪氨酸信号对PKM 2的调节将葡萄糖代谢产物从能量产生转移到合成代谢过程。总的来说，我们的结果表明，这种磷酸酪氨酸结合形式的丙酮酸激酶的表达对于癌细胞的快速生长至关重要。
Growth factors stimulate cells to take up excess nutrients and to use them for anabolic processes. The biochemical mechanism by which this is accomplished is not fully understood but it is initiated by phosphorylation of signalling proteins on tyrosine residues. Using a novel proteomic screen for phosphotyrosine- binding proteins, we have made the observation that an enzyme involved in glycolysis, the human M2 ( fetal) isoform of pyruvate kinase ( PKM2), binds directly and selectively to tyrosine- phosphorylated peptides. We show that binding of phosphotyrosine peptides to PKM2 results in release of the allosteric activator fructose- 1,6- bisphosphate, leading to inhibition of PKM2 enzymatic activity. We also provide evidence that this regulation of PKM2 by phosphotyrosine signalling diverts glucose metabolites from energy production to anabolic processes when cells are stimulated by certain growth factors. Collectively, our results indicate that expression of this phosphotyrosine- binding form of pyruvate kinase is critical for rapid growth in cancer cells.