anti-atherosclerotic and anti-cancer effects of AMPK activation

2016 Fiscal Year Final Research Report

• Project/Area Number: 26461108
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Osaka University
• Principal Investigator: Tsukamoto Osamu 大阪大学, 医学系研究科, 助教 (80589151)
• Co-Investigator(Renkei-kenkyūsha): SHINTANI Yasunori 大阪大学, 大学院医学系研究科, 助教 (20712243) ; HIGO Shuichiro 大阪大学, 大学院医学系研究科, 助教 (00604034) ; KATO Hisakazu 大阪大学, 大学院医学系研究科, 助教 (00604034)
• Research Collaborator: Yan Yi 大阪大学, 大学院医学系研究科, 大学院生
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: AMPK / PDLIM5 / cell migration

Outline of Final Research Achievements

We identified Pdlim5 as a novel AMPK substrate. AMPK phosphorylates Pdlim5 at Ser177. To investigate the role of Ser177 phosphorylation by AMPK, we produced the knockdown-and-rescue (KDR) system of vSMCs, in which endogenous Pdlim5 were replaced by exogenous EGFP-tagged-Pdlim5s. KDR/S177D-Pdlim5 cells exhibited perturbed cell migration compared with KDR/wild-type- and KDR/S177A-Pdlim5 cells even in the absence of AMPK activator. Furthermore, KDR/S177D-Pdlim5 cells exhibited defective lamellipodia formation. Consistent with this, KDR/S177D-Pdlim5 cells exhibited dislocation of Arp2/3 complex from the leading edge to cytosol and suppressed Rac1 activity. Finally, KDR/S177D-Pdlim5 cells disrupted the physical association with Arhgeg6, a guanine nucleotide exchange factor for Rac1. In conclusion, enhanced AMPK activation inhibits cell migration by interfering lamellipodia formation by suppressing the Arhgef6-Rac1-Arp2/3 signaling pathway via phosphorylating Pdlim5.

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