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

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 and Seiji Takashima
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Yi Yan: Osaka University Graduate School of Medicine
Osamu Tsukamoto: Osaka University Graduate School of Medicine
Atsushi Nakano: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute
Hisakazu Kato: Osaka University Graduate School of Medicine
Hidetaka Kioka: Osaka University Graduate School of Medicine
Noriaki Ito: Osaka University Graduate School of Medicine
Shuichiro Higo: Osaka University Graduate School of Medicine
Satoru Yamazaki: National Cerebral and Cardiovascular Center Research Institute
Yasunori Shintani: Osaka University Graduate School of Medicine
Ken Matsuoka: Osaka University Graduate School of Medicine
Yulin Liao: Nanfang Hospital, Southern Medical University
Hiroshi Asanuma: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute
Masanori Asakura: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute
Kazuaki Takafuji: Center for Research Education, Osaka University Graduate School of Medicine
Tetsuo Minamino: Osaka University Graduate School of Medicine
Yoshihiro Asano: Osaka University Graduate School of Medicine
Masafumi Kitakaze: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute
Seiji Takashima: Osaka University Graduate School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms7137

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