ADP-ribosylation factor 6 (Arf6) is an important regulator of membrane trafficking and cytoskeletal dynamics at the plasma membrane that promotes cancer cell migration and invasiveness. Arf proteins are activated by guanine-nucleotide-exchange factors (GEFs), and Fang-Jen Lee and colleagues have previously demonstrated that Arf3 can be activated by Snf1, the yeast homologue of AMP-activated protein kinase (AMPK), a key regulator of cellular metabolism. Here, Snf1 acts as a non-canonical GEF for Arf3. In this study (Chen et al., 2022), the authors develop this work by demonstrating that AMPK functions as a non-canonical GEF for Arf6 activation during glucose deprivation in mammalian cells, suggesting an evolutionarily conserved role. Here, activation of Arf6 by AMPK increases cell migration and invasion of ovarian cancer cells both in vitro and in vivo. Concurrently, siRNA-mediated knockdown of AMPK reduces levels of Arf6-GTP. The authors also identify the binding motif of AMPK responsible for Arf6 activation; interestingly, this involves the C-terminal region of the catalytic subunit of AMPK but does not require its kinase activity. Taken together, these results highlight AMPK as a novel GEF in the activation of Arf6 during energy deprivation and enhance our understanding of the role of AMPK in promoting ovarian cancer migration and invasion.
