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

• DOI: 10.1038/ncomms7137
• Publication Date: 2015-01-30T14:00:31Z
• Authors: Yi Yan; Osamu Tsukamoto; Atsushi Nakano; Hisakazu Kato; Hidetaka Kioka; Noriaki Ito; Shuichiro Higo; Satoru Yamazaki; Yasunori Shintani; Ken Matsuoka; Yulin Liao; Hiroshi Asanuma; Masanori Asakura; Kazuaki Takafuji; Tetsuo Minamino; Yoshihiro Asano; Masafumi Kitakaze; Seiji Takashima
• Keywords: rac1 GTP-Binding Protein; 0301 basic medicine; Microfilament Proteins; AMP-Activated Protein Kinases; Article; Actin-Related Protein 2-3 Complex; Cell Line; Mice; 03 medical and health sciences; Cell Movement; Animals; Phosphorylation; Adaptor Proteins, Signal Transducing; Signal Transduction

AbstractAugmented 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.