title: Augmented AMPK activity inhibits cell migration by phosphorylating the novel substrate Pdlim5.
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.
authors: Department of Medical Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yi
authors: Y
authors: Yan
authors: Department of Medical Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Osamu
authors: O
authors: Tsukamoto
authors: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Atsushi
authors: A
authors: Nakano
authors: Department of Medical Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Hisakazu
authors: H
authors: Kato
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Hidetaka
authors: H
authors: Kioka
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Noriaki
authors: N
authors: Ito
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Shuichiro
authors: S
authors: Higo
authors: Department of Cell Biology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Satoru
authors: S
authors: Yamazaki
authors: Department of Medical Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yasunori
authors: Y
authors: Shintani
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Ken
authors: K
authors: Matsuoka
authors: Department of Cardiology, Nanfang Hospital, Southern Medical University, 1838 North Guangzhou Avenue, 510515 Guangzhou, China.
authors: Yulin
authors: Y
authors: Liao
authors: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Hiroshi
authors: H
authors: Asanuma
authors: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Masanori
authors: M
authors: Asakura
authors: Center for Research Education, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Kazuaki
authors: K
authors: Takafuji
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Tetsuo
authors: T
authors: Minamino
authors: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yoshihiro
authors: Y
authors: Asano
authors: Depertment of Clinical Research and Development, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan.
authors: Masafumi
authors: M
authors: Kitakaze
authors: 1] Department of Medical Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan [2] Japan Science and Technology Agency-Core Research for Evolutional Science and Technology (CREST), Kawaguchi 332-0012, Japan.
authors: Seiji
authors: S
authors: Takashima
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D048868:Adaptor Proteins, Signal Transducing; C510085:ENH protein, mouse; D008840:Microfilament Proteins; D055372:AMP-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein
references: J Cell Biol. 2004 May 24;165(4):539-51
references: 15159419
references: Cell. 2011 Jun 24;145(7):1012-22
references: 21703446
references: BMC Cell Biol. 2008;9:65
references: 19068115
references: J Cell Biol. 1999 Nov 29;147(5):1009-22
references: 10579721
references: Nature. 2009 Sep 3;461(7260):104-8
references: 19693014
references: J Cell Biol. 2006 May 8;173(3):383-94
references: 16651381
references: FASEB J. 2011 Dec;25(12):4358-68
references: 21885655
references: EMBO J. 2010 Jan 20;29(2):281-91
references: 20033063
references: Biol Cell. 2007 Sep;99(9):489-502
references: 17696879
references: Nature. 2007 Jun 21;447(7147):1017-20
references: 17486097
references: JAMA. 2008 Apr 2;299(13):1561-73
references: 18378631
references: J Virol. 2013 Jan;87(2):746-55
references: 23115293
references: Mol Med Rep. 2012 Apr;5(4):1068-74
references: 22246099
references: Cell Metab. 2013 Jan 8;17(1):113-24
references: 23274086
references: J Am Coll Cardiol. 2011 May 17;57(20):2035-6
references: 21565645
references: Hum Mol Genet. 2003 Jan 15;12(2):155-67
references: 12499396
references: Cancer Sci. 2012 Apr;103(4):614-9
references: 22188216
references: Cell. 2012 Mar 2;148(5):973-87
references: 22385962
references: J Cell Biol. 2003 Jul 21;162(2):223-32
references: 12860967
references: J Cell Biol. 2012 Apr 16;197(2):239-51
references: 22492726
references: Mol Cell Biol. 2006 Jul;26(14):5336-47
references: 16809770
references: Nat Chem Biol. 2011 Aug;7(8):512-8
references: 21769098
references: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17272-7
references: 17088526
references: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18289-94
references: 22021442
references: PLoS One. 2013;8(4):e59320
references: 23593136
references: Nat Rev Mol Cell Biol. 2010 Sep;11(9):633-43
references: 20729930
references: Biochem Biophys Res Commun. 2000 Jun 7;272(2):505-12
references: 10833443
references: ScientificWorldJournal. 2007;7:1470-92
references: 17767364
references: Proc Natl Acad Sci U S A. 2006 Mar 28;103(13):4976-81
references: 16549780
references: FEBS Lett. 2008 Apr 9;582(8):1189-96
references: 18325335
references: EMBO J. 2004 Sep 1;23(17):3492-504
references: 15306850
references: Cell. 2008 Oct 31;135(3):510-23
references: 18984162
references: J Cell Biol. 2001 Jan 8;152(1):111-26
references: 11149925
references: Genes Cells. 2004 Mar;9(3):193-204
references: 15005707
references: Rev Diabet Stud. 2009 Spring;6(1):13-36
references: 19557293
references: Nat Cell Biol. 2010 Jun;12(6):583-90
references: 20495555
references: Circ Res. 2010 Aug 6;107(3):348-56
references: 20538684
references: Front Biosci (Landmark Ed). 2009;14:19-44
references: 19273052
references: Cardiovasc Drugs Ther. 2008 Jun;22(3):215-24
references: 18288595
references: Science. 2003 Dec 5;302(5651):1704-9
references: 14657486
references: Cell. 2006 Jan 27;124(2):423-35
references: 16439214
references: Nat Rev Cancer. 2010 Dec;10(12):858-70
references: 21102636
references: Nat Rev Mol Cell Biol. 2010 Apr;11(4):237-51
references: 20237478