Université Paris-Saclay, Faculté des Sciences d'Orsay, CNRS UMR 3347, INSERM U1021, Orsay, France.
Institut Curie Research Division, PSL Research University, CNRS UMR 3347, INSERM U1021, Orsay, France.
Life Sci Alliance. 2022 Aug 1;5(12):e202201377. doi: 10.26508/lsa.202201377.
Cell migration is a complex process, tightly regulated during embryonic development and abnormally activated during cancer metastasis. RAS-dependent signaling is a major nexus controlling essential cell parameters including proliferation, survival, and migration, utilizing downstream effectors such as the PI3K/AKT signaling pathway. In melanoma, oncogenic mutations frequently enhance RAS, PI3K/AKT, or MAP kinase signaling and trigger other cancer hallmarks among which the activation of metabolism regulators. PFKFB4 is one of these critical regulators of glycolysis and of the Warburg effect. Here, however, we explore a novel function of PFKFB4 in melanoma cell migration. We find that PFKFB4 interacts with ICMT, a posttranslational modifier of RAS. PFKFB4 promotes ICMT/RAS interaction, controls RAS localization at the plasma membrane, activates AKT signaling and enhances cell migration. We thus provide evidence of a novel and glycolysis-independent function of PFKFB4 in human cancer cells. This unconventional activity links the metabolic regulator PFKFB4 to RAS-AKT signaling and impacts melanoma cell migration.
细胞迁移是一个复杂的过程，在胚胎发育过程中受到严格调控，在癌症转移过程中异常激活。RAS 依赖性信号是控制包括增殖、存活和迁移在内的基本细胞参数的主要枢纽，利用下游效应器如 PI3K/AKT 信号通路。在黑色素瘤中，致癌突变经常增强 RAS、PI3K/AKT 或 MAP 激酶信号，并触发其他癌症特征，其中包括代谢调节剂的激活。PFKFB4 是糖酵解和瓦伯格效应的关键调节因子之一。然而，在这里，我们探索了 PFKFB4 在黑色素瘤细胞迁移中的一个新功能。我们发现 PFKFB4 与 ICMT 相互作用，ICMT 是 RAS 的一种翻译后修饰物。PFKFB4 促进 ICMT/RAS 相互作用，控制 RAS 在质膜上的定位，激活 AKT 信号并增强细胞迁移。因此，我们为 PFKFB4 在人类癌细胞中具有新的、与糖酵解无关的功能提供了证据。这种非传统的活性将代谢调节剂 PFKFB4 与 RAS-AKT 信号联系起来，并影响黑色素瘤细胞的迁移。
