Subcellular regulation of glucose metabolism through multienzyme glucosome assemblies by EGF-ERK1/2 signaling pathways.
Subcellular regulation of glucose metabolism through multienzyme glucosome assemblies by EGF-ERK1/2 signaling pathways.
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DOI：
10.1016/j.jbc.2022.101675
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
An S
中科院分区：
文献类型：
--
作者：
Jeon M;Chauhan KM;Szeto GL;Kyoung M;An S
人类葡萄糖代谢的多酶代谢组件，即糖小体，先前已被证明以组装大小依赖的方式在糖酵解和构建块生物合成之间分配葡萄糖通量。在三种不同大小的糖小体组合中，我们已经证明，在表皮生长因子（EGF）存在的情况下，大尺寸的糖小体在功能上与促进丝氨酸的生物合成有关。然而，由于EGF在信号通路中的多功能作用，目前尚不清楚哪些EGF介导的信号通路促进了癌细胞中这些大型糖小体的聚集。在这项研究中，我们使用Luminex多路复用实验和高含量单细胞成像来证明EGF在Hs578T细胞中触发细胞外信号调节激酶1/2 （ERK1/2）的时间激活。随后，我们发现使用ERK1/2药理学抑制剂、SCH772984或靶向ERK1/2的短发夹rna治疗可促进Hs578T细胞中大尺寸组装体向中等尺寸组装体的解离。此外，我们的Western blot分析显示，EGF处理不会增加参与葡萄糖代谢和丝氨酸生物合成的酶的表达水平。观察到的糖小体在大尺寸和中等尺寸之间的空间转换似乎是由糖小体酶的动态分配程度介导的，而不改变它们的表达水平。总之，我们的研究表明，EGF-ERK1/2信号通路在癌细胞中上调大尺寸葡萄糖体中发挥重要作用，从而在功能上调控糖酵解衍生的丝氨酸生物合成的促进。
A multienzyme metabolic assembly for human glucose metabolism, namely the glucosome, has been previously demonstrated to partition glucose flux between glycolysis and building block biosynthesis in an assembly size-dependent manner. Among three different sizes of glucosome assemblies, we have shown that large-sized glucosomes are functionally associated with the promotion of serine biosynthesis in the presence of epidermal growth factor (EGF). However, due to multifunctional roles of EGF in signaling pathways, it is unclear which EGF-mediated signaling pathways promote these large glucosome assemblies in cancer cells. In this study, we used Luminex multiplexing assays and high-content single-cell imaging to demonstrate that EGF triggers temporal activation of extracellular signal-regulated kinases 1/2 (ERK1/2) in Hs578T cells. Subsequently, we found that treatments with a pharmacological inhibitor of ERK1/2, SCH772984, or short-hairpin RNAs targeting ERK1/2 promote the dissociation of large-sized assemblies to medium-sized assemblies in Hs578T cells. In addition, our Western blot analyses revealed that EGF treatment does not increase the expression levels of enzymes that are involved in both glucose metabolism and serine biosynthesis. The observed spatial transition of glucosome assemblies between large and medium sizes appears to be mediated by the degree of dynamic partitioning of glucosome enzymes without changing their expression levels. Collectively, our study demonstrates that EGF–ERK1/2 signaling pathways play an important role in the upregulation of large-sized glucosomes in cancer cells, thus functionally governing the promotion of glycolysis-derived serine biosynthesis.
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