Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5

• Published in: Nature communications Vol. 6; no. 1; p. 6137
• Main Authors: Yan, Yi, Tsukamoto, Osamu, Nakano, Atsushi, Kato, Hisakazu, Kioka, Hidetaka, Ito, Noriaki, Higo, Shuichiro, Yamazaki, Satoru, Shintani, Yasunori, Matsuoka, Ken, Liao, Yulin, Asanuma, Hiroshi, Asakura, Masanori, Takafuji, Kazuaki, Minamino, Tetsuo, Asano, Yoshihiro, Kitakaze, Masafumi, Takashima, Seiji
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30-01-2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 13/109; 13/51; 13/89; 14/1; 14/19; 14/33; 14/35; 42/109; 631/80/458/1733; 631/80/84; 631/80/84/1756; 631/80/86; 82/1; 82/16; 82/29; 82/80; 82/81; 82/83; Actin-Related Protein 2-3 Complex - metabolism; Adaptor Proteins, Signal Transducing - metabolism; AMP-Activated Protein Kinases - metabolism; Animals; Cell Line; Cell Movement - physiology; Humanities and Social Sciences; Mice; Microfilament Proteins - metabolism; multidisciplinary; Phosphorylation; rac1 GTP-Binding Protein - metabolism; Science; Science (multidisciplinary); Signal Transduction - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms7137

Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration, possibly contributing to the clinical benefits of chemical AMPK activators in preventing atherosclerosis, vascular remodelling and cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we identify PDZ and LIM domain 5 (Pdlim5) as a novel AMPK substrate and show that it plays a critical role in the inhibition of cell migration. AMPK directly phosphorylates Pdlim5 at Ser177. Exogenous expression of phosphomimetic S177D-Pdlim5 inhibits cell migration and attenuates lamellipodia formation. Consistent with this observation, S177D-Pdlim5 suppresses Rac1 activity at the cell periphery and displaces the Arp2/3 complex from the leading edge. Notably, S177D-Pdlim5, but not WT-Pdlim5, attenuates the association with Rac1-specific guanine nucleotide exchange factors at the cell periphery. Taken together, our findings indicate that phosphorylation of Pdlim5 on Ser177 by AMPK mediates inhibition of cell migration by suppressing the Rac1-Arp2/3 signalling pathway.
Augmented AMP-activated protein kinase (AMPK) activity inhibits cell migration through an unknown mechanism. Here, Yan
et al.
show that AMPK phosphorylates the novel substrate PDZ and LIM domain 5 (Pdlim5), and that phosphomimetic Pdlim5 impairs cell migration by disrupting the Rac1-Arp2/3 signalling pathway.