Department of Biochemistry and Molecular Genetics, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
Metabolomics Core Facility, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
Mol Cell. 2020 Jun 18;78(6):1178-1191.e6. doi: 10.1016/j.molcel.2020.05.001. Epub 2020 Jun 1.
The RAS-ERK/MAPK (RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase) pathway integrates growth-promoting signals to stimulate cell growth and proliferation, at least in part, through alterations in metabolic gene expression. However, examples of direct and rapid regulation of the metabolic pathways by the RAS-ERK pathway remain elusive. We find that physiological and oncogenic ERK signaling activation leads to acute metabolic flux stimulation through the de novo purine synthesis pathway, thereby increasing building block availability for RNA and DNA synthesis, which is required for cell growth and proliferation. We demonstrate that ERK2, but not ERK1, phosphorylates the purine synthesis enzyme PFAS (phosphoribosylformylglycinamidine synthase) at T619 in cells to stimulate de novo purine synthesis. The expression of nonphosphorylatable PFAS (T619A) decreases purine synthesis, RAS-dependent cancer cell-colony formation, and tumor growth. Thus, ERK2-mediated PFAS phosphorylation facilitates the increase in nucleic acid synthesis required for anabolic cell growth and proliferation.
RAS-ERK/MAPK（RAS-extracellular signal-regulated kinase/mitogen-activated protein kinase）通路整合了促进生长的信号，通过改变代谢基因表达，至少部分地刺激细胞生长和增殖。然而，RAS-ERK 通路直接和快速调节代谢途径的例子仍然难以捉摸。我们发现，生理和致癌 ERK 信号的激活通过从头嘌呤合成途径导致急性代谢通量刺激，从而增加 RNA 和 DNA 合成所需的构建块可用性，这是细胞生长和增殖所必需的。我们证明 ERK2 而不是 ERK1 在细胞中磷酸化嘌呤合成酶 PFAS（磷酸核糖基甲酰胺基甘氨酸合酶）在 T619 处以刺激从头嘌呤合成。非磷酸化 PFAS（T619A）的表达减少嘌呤合成、RAS 依赖性癌细胞集落形成和肿瘤生长。因此，ERK2 介导的 PFAS 磷酸化促进了合成代谢细胞生长和增殖所需的核酸合成的增加。
