Department of Haematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Nat Commun. 2013;4:1790. doi: 10.1038/ncomms2759.
How oncogenic signalling coordinates glycolysis and anabolic biosynthesis in cancer cells remains unclear. We recently reported that the glycolytic enzyme phosphoglycerate mutase 1 (PGAM1) regulates anabolic biosynthesis by controlling intracellular levels of its substrate 3-phosphoglycerate and product 2-phosphoglycerate. Here we report a novel mechanism in which Y26 phosphorylation enhances PGAM1 activation through release of inhibitory E19 that blocks the active site, stabilising cofactor 2,3-bisphosphoglycerate binding and H11 phosphorylation. We also report the crystal structure of H11-phosphorylated PGAM1 and find that phospho-H11 activates PGAM1 at least in part by promoting substrate 3-phosphoglycerate binding. Moreover, Y26 phosphorylation of PGAM1 is common in human cancer cells and contributes to regulation of 3-phosphoglycerate and 2-phosphoglycerate levels, promoting cancer cell proliferation and tumour growth. As PGAM1 is a negative transcriptional target of TP53, and is therefore commonly upregulated in human cancers, these findings suggest that Y26 phosphorylation represents an additional acute mechanism underlying phosphoglycerate mutase 1 upregulation.
致癌信号如何协调癌细胞中的糖酵解和合成代谢生物合成仍不清楚。我们最近报道称，糖酵解酶磷酸甘油酸变位酶 1（PGAM1）通过控制其底物 3-磷酸甘油酸和产物 2-磷酸甘油酸的细胞内水平来调节合成代谢生物合成。在这里，我们报告了一种新的机制，即 Y26 磷酸化通过释放抑制 E19 来增强 PGAM1 的激活，E19 阻止了活性位点，稳定了辅助因子 2,3-二磷酸甘油酸结合和 H11 磷酸化。我们还报告了 H11 磷酸化 PGAM1 的晶体结构，并发现磷酸化 H11 通过促进底物 3-磷酸甘油酸结合至少部分激活 PGAM1。此外，PGAM1 的 Y26 磷酸化在人类癌细胞中很常见，有助于调节 3-磷酸甘油酸和 2-磷酸甘油酸水平，促进癌细胞增殖和肿瘤生长。由于 PGAM1 是 TP53 的负转录靶标，因此在人类癌症中通常上调，这些发现表明 Y26 磷酸化代表了磷酸甘油酸变位酶 1 上调的另一种急性机制。
