AMPK promotes Arf6 activation in a kinase-independent manner upon glucose starvation
- J Cell Sci. 2022 Sep 15;135(18):jcs259609. doi: 10.1242/jcs.259609.
- 1. Institute of Molecular Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
- 2. Center of Precision Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
- 3. Institute of Biochemical Sciences, College of Life Science, National Taiwan University, Taipei 106, Taiwan.
- 4. Institute of Biological Chemistry, Academia Sinica, Taipei 115, Taiwan.
- 5. Department of Medical Research, National Taiwan University Hospital, Taipei 100, Taiwan.
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.