Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
J Cell Sci. 2022 Sep 15;135(18). doi: 10.1242/jcs.259609. Epub 2022 Sep 14.
AMP-activated protein kinase (AMPK) is a crucial cellular nutrient and energy sensor that maintains energy homeostasis. AMPK also governs cancer cell invasion and migration by regulating gene expression and activating multiple cellular signaling pathways. ADP-ribosylation factor 6 (Arf6) can be activated via nucleotide exchange by guanine-nucleotide-exchange factors (GEFs), and its activation also regulates tumor invasion and migration. By studying GEF-mediated Arf6 activation, we have elucidated that AMPK functions as a noncanonical GEF for Arf6 in a kinase-independent manner. Moreover, by examining the physiological role of the AMPK-Arf6 axis, we have determined that AMPK activates Arf6 upon glucose starvation and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) treatment. We have further identified the binding motif in the C-terminal regulatory domain of AMPK that is responsible for promoting Arf6 activation and, thus, inducing cell migration and invasion. These findings reveal a noncanonical role of AMPK in which its C-terminal regulatory domain serves as a GEF for Arf6 during glucose deprivation.
AMP 激活的蛋白激酶 (AMPK) 是一种重要的细胞营养和能量传感器，可维持能量平衡。AMPK 还通过调节基因表达和激活多种细胞信号通路来控制癌细胞的侵袭和迁移。ADP-核糖基化因子 6 (Arf6) 可以通过鸟嘌呤核苷酸交换因子 (GEFs) 的核苷酸交换而被激活，其激活还调节肿瘤侵袭和迁移。通过研究 GEF 介导的 Arf6 激活，我们已经阐明了 AMPK 以激酶非依赖性的方式作为 Arf6 的非典型 GEF。此外，通过检查 AMPK-Arf6 轴的生理作用，我们确定 AMPK 在葡萄糖饥饿和 5-氨基咪唑-4-甲酰胺-1-β-D-核糖呋喃糖苷 (AICAR) 处理时激活 Arf6。我们进一步确定了 AMPK 羧基末端调节结构域中负责促进 Arf6 激活并由此诱导细胞迁移和侵袭的结合基序。这些发现揭示了 AMPK 的一种非典型作用，即其羧基末端调节结构域在葡萄糖剥夺期间作为 Arf6 的 GEF。
