title: Redox-relevant aspects of the extracellular matrix and its cellular contacts via integrins.
abstract: CONCLUSIONS
  The extracellular matrix (ECM) fulfills essential functions in multicellular organisms. It provides the mechanical scaffold and environmental cues to cells. Upon cell attachment, the ECM signals into the cells. In this process, reactive oxygen species (ROS) are physiologically used as signalizing molecules.
  
  
  BACKGROUND
  ECM attachment influences the ROS-production of cells. In turn, ROS affect the production, assembly and turnover of the ECM during wound healing and matrix remodeling. Pathological changes of ROS levels lead to excess ECM production and increased tissue contraction in fibrotic disorders and desmoplastic tumors. Integrins are cell adhesion molecules which mediate cell adhesion and force transmission between cells and the ECM. They have been identified as a target of redox-regulation by ROS. Cysteine-based redox-modifications, together with structural data, highlighted particular regions within integrin heterodimers that may be subject to redox-dependent conformational changes along with an alteration of integrin binding activity.
  
  
  RESULTS
  In a molecular model, a long-range disulfide-bridge within the integrin β-subunit and disulfide bridges within the genu and calf-2 domains of the integrin α-subunit may control the transition between the bent/inactive and upright/active conformation of the integrin ectodomain. These thiol-based intramolecular cross-linkages occur in the stalk domain of both integrin subunits, whereas the ligand-binding integrin headpiece is apparently unaffected by redox-regulation.
  
  
  CONCLUSIONS
  Redox-regulation of the integrin activation state may explain the effect of ROS in physiological processes. A deeper understanding of the underlying mechanism may open new prospects for the treatment of fibrotic disorders.
authors.affiliation: 1 Institute for Physiological Chemistry and Pathobiochemistry, University of Münster , Münster, Germany .
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Eble
authors.forename: Flávia Figueiredo
authors.initials: FF
authors.lastname: de Rezende
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002477:Cells / Q000166:cytology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D016023:Integrins / Q000378:metabolism*; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D016023:Integrins; D017382:Reactive Oxygen Species
references.citation: Biochemistry. 2003 Nov 11;42(44):12950-9
references.pmid: 14596610
references.citation: Annu Rev Cell Dev Biol. 1996;12:697-715
references.pmid: 8970741
references.citation: Matrix Biol. 2000 Aug;19(4):325-32
references.pmid: 10963993
references.citation: Blood. 2002 Oct 1;100(7):2472-8
references.pmid: 12239158
references.citation: Curr Opin Hematol. 2012 May;19(3):212-7
references.pmid: 22395664
references.citation: J Thromb Haemost. 2006 Dec;4(12):2533-41
references.pmid: 17002656
references.citation: J Biol Chem. 2010 Dec 3;285(49):38428-37
references.pmid: 20884611
references.citation: Atherosclerosis. 2003 Mar;167(1):45-53
references.pmid: 12618267
references.citation: J Clin Invest. 1996 Dec 1;98(11):2572-9
references.pmid: 8958220
references.citation: Antioxid Redox Signal. 2014 May 1;20(13):2074-89
references.pmid: 24206201
references.citation: IUBMB Life. 2011 Jul;63(7):538-46
references.pmid: 21698758
references.citation: Proc Natl Acad Sci U S A. 2010 Dec 28;107(52):22481-6
references.pmid: 21156831
references.citation: Matrix Biol. 2000 Aug;19(4):319-23
references.pmid: 10963992
references.citation: J Thromb Haemost. 2011 Jun;9(6):1207-15
references.pmid: 21645227
references.citation: Eur J Dermatol. 2006 Jul-Aug;16(4):375-9
references.pmid: 16935793
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):14737-41
references.pmid: 14657342
references.citation: Dev Dyn. 2002 Apr;223(4):497-516
references.pmid: 11921338
references.citation: Am J Respir Crit Care Med. 1998 Dec;158(6):1920-8
references.pmid: 9847287
references.citation: Antioxid Redox Signal. 2007 Apr;9(4):469-81
references.pmid: 17280488
references.citation: Cold Spring Harb Symp Quant Biol. 1992;57:249-58
references.pmid: 1339663
references.citation: Cell Cycle. 2012 Jun 1;11(11):2084-91
references.pmid: 22580469
references.citation: Cell. 2011 Mar 4;144(5):646-74
references.pmid: 21376230
references.citation: Biochemistry. 2010 Nov 30;49(47):10158-65
references.pmid: 21038860
references.citation: Am J Pathol. 2012 Apr;180(4):1340-55
references.pmid: 22387320
references.citation: J Biol Chem. 2003 Feb 28;278(9):7270-7
references.pmid: 12496264
references.citation: Respir Physiol Neurobiol. 2010 Dec 31;174(3):299-306
references.pmid: 20804863
references.citation: Curr Pharm Des. 2005;11(7):867-80
references.pmid: 15777240
references.citation: Nat Struct Biol. 2002 Apr;9(4):282-7
references.pmid: 11896403
references.citation: Int J Cell Biol. 2012;2012:762825
references.pmid: 22666258
references.citation: J Biol Chem. 2001 Oct 19;276(42):38628-35
references.pmid: 11507099
references.citation: Circulation. 2005 Jun 7;111(22):2973-80
references.pmid: 15927968
references.citation: Cell Tissue Res. 2010 Jan;339(1):247-57
references.pmid: 19693541
references.citation: Antioxid Redox Signal. 2011 Jan 1;14(1):1-7
references.pmid: 20690882
references.citation: Exp Cell Res. 2012 May 15;318(9):973-8
references.pmid: 22410250
references.citation: Blood. 2007 Oct 1;110(7):2475-83
references.pmid: 17615290
references.citation: Int J Dev Biol. 2011;55(4-5):511-25
references.pmid: 21769776
references.citation: FEBS J. 2011 Jan;278(1):28-45
references.pmid: 21087458
references.citation: Antioxid Redox Signal. 2014 May 1;20(13):2043-58
references.pmid: 24070031
references.citation: Curr Opin Pharmacol. 2008 Apr;8(2):153-9
references.pmid: 18243791
references.citation: Cell Mol Life Sci. 2006 Oct;63(19-20):2304-16
references.pmid: 16909208
references.citation: Blood. 2002 Sep 15;100(6):2094-101
references.pmid: 12200372
references.citation: Nat Rev Drug Discov. 2003 Sep;2(9):703-16
references.pmid: 12951577
references.citation: J Cell Biol. 2009 Aug 24;186(4):589-600
references.pmid: 19704023
references.citation: Mol Cell. 2008 May 23;30(4):393-402
references.pmid: 18498744
references.citation: Free Radic Biol Med. 2012 Aug 1;53(3):521-31
references.pmid: 22659335
references.citation: Cell Mol Life Sci. 1999 Oct 30;56(5-6):427-41
references.pmid: 11212296
references.citation: J Biol Chem. 2006 May 19;281(20):14100-10
references.pmid: 16569638
references.citation: J Pathol. 2013 Jan;229(2):298-309
references.pmid: 22996908
references.citation: Am J Pathol. 1994 Dec;145(6):1411-20
references.pmid: 7992844
references.citation: Exp Cell Res. 2008 Feb 1;314(3):489-97
references.pmid: 18045589
references.citation: Microsc Res Tech. 2008 May;71(5):357-70
references.pmid: 18219669
references.citation: EMBO J. 2010 Feb 3;29(3):666-79
references.pmid: 20033057
references.citation: Antioxid Redox Signal. 2014 May 1;20(13):2011-25
references.pmid: 23901911
references.citation: Cell Tissue Res. 2010 Jan;339(1):7-18
references.pmid: 19756756
references.citation: J Biol Chem. 2000 Mar 10;275(10):7249-60
references.pmid: 10702295
references.citation: Biol Chem. 2013 Apr;394(4):435-48
references.pmid: 23324380
references.citation: Annu Rev Cell Dev Biol. 2005;21:381-410
references.pmid: 16212500
references.citation: Nat Rev Mol Cell Biol. 2010 Apr;11(4):288-300
references.pmid: 20308986
references.citation: Thromb Haemost. 2002 Jul;88(1):104-10
references.pmid: 12152649
references.citation: Biochem J. 2004 Mar 15;378(Pt 3):1079-82
references.pmid: 14690453
references.citation: Curr Pharm Des. 2009;15(12):1277-94
references.pmid: 19355968
references.citation: Scand J Immunol. 2011 May;73(5):420-7
references.pmid: 21204900
references.citation: J Mol Med (Berl). 2009 Mar;87(3):261-72
references.pmid: 19034402
references.citation: Nat Rev Mol Cell Biol. 2012 Oct;13(10):616-30
references.pmid: 22992590
references.citation: Circ Res. 2003 Jun 13;92(11):e80-6
references.pmid: 12750313
references.citation: Birth Defects Res C Embryo Today. 2010 Mar;90(1):8-31
references.pmid: 20301220
references.citation: Biomaterials. 2013 May;34(15):3807-15
references.pmid: 23465490
references.citation: J Biol Chem. 2013 Apr 12;288(15):10819-29
references.pmid: 23423382
references.citation: Cell Tissue Res. 2010 Jan;339(1):269-80
references.pmid: 19693543
references.citation: Comp Biochem Physiol C Toxicol Pharmacol. 2004 Oct;139(1-3):119-26
references.pmid: 15556073
references.citation: Curr Opin Chem Biol. 2008 Feb;12(1):18-24
references.pmid: 18282483
references.citation: Biochemistry. 2010 Feb 9;49(5):835-42
references.pmid: 20050630
references.citation: Exp Ther Med. 2012 Sep;4(3):355-362
references.pmid: 23181099
references.citation: Eur J Biochem. 1984 Aug 1;142(3):493-502
references.pmid: 6432530
references.citation: Annu Rev Cell Dev Biol. 2010;26:397-419
references.pmid: 20690820
references.citation: J Biol Chem. 2005 Aug 26;280(34):30586-93
references.pmid: 15965234
references.citation: J Immunol. 1998 Dec 1;161(11):6323-9
references.pmid: 9834122
references.citation: Trends Cell Biol. 2008 Nov;18(11):560-74
references.pmid: 18848450
references.citation: Blood. 2003 Oct 1;102(7):2491-7
references.pmid: 12816866
references.citation: Cell. 2000 Mar 31;101(1):47-56
references.pmid: 10778855
references.citation: Nat Med. 2002 Sep;8(9):918-21
references.pmid: 12205444
references.citation: J Cell Sci. 2006 Oct 1;119(Pt 19):3901-3
references.pmid: 16988024
references.citation: Eur J Immunol. 2003 Sep;33(9):2599-608
references.pmid: 12938236
references.citation: J Cell Physiol. 2010 Oct;225(1):52-62
references.pmid: 20648623
references.citation: J Cell Physiol. 1993 Nov;157(2):408-12
references.pmid: 8227170
references.citation: Cold Spring Harb Perspect Biol. 2011 Jan 01;3(1):a004978
references.pmid: 21421911
references.citation: J Biol Chem. 1984 Mar 25;259(6):3955-61
references.pmid: 6368554
references.citation: Cardiovasc Res. 2008 Nov 1;80(2):299-308
references.pmid: 18567639
references.citation: J Biol Chem. 2008 Aug 29;283(35):24061-76
references.pmid: 18559349
references.citation: Cell. 2003 Jan 10;112(1):99-111
references.pmid: 12526797
references.citation: J Cell Biol. 2007 Dec 17;179(6):1311-23
references.pmid: 18086923
references.citation: J Biol Chem. 2000 May 12;275(19):14139-46
references.pmid: 10799490
references.citation: Curr Opin Cell Biol. 2004 Oct;16(5):558-64
references.pmid: 15363807
references.citation: Methods Enzymol. 1987;144:475-89
references.pmid: 2442581
references.citation: Int J Colorectal Dis. 2013 Jul;28(7):915-24
references.pmid: 23271497
references.citation: Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2961-6
references.pmid: 9501198
references.citation: Kidney Int. 2011 May;79(9):944-56
references.pmid: 21307839
references.citation: EMBO J. 1993 Dec;12(12):4795-802
references.pmid: 8223488
references.citation: Nature. 2004 Nov 4;432(7013):59-67
references.pmid: 15378069
references.citation: J Biol Chem. 2012 Mar 16;287(12):8879-91
references.pmid: 22308022
references.citation: Cell. 2002 Sep 20;110(6):673-87
references.pmid: 12297042
references.citation: Am J Clin Nutr. 1978 Jul;31(7):1221-36
references.pmid: 27088
references.citation: FEBS J. 2008 Apr;275(8):1813-23
references.pmid: 18331351
references.citation: Int J Mol Med. 2005 Oct;16(4):677-81
references.pmid: 16142404
references.citation: Age (Dordr). 2009 Dec;31(4):305-25
references.pmid: 19588272
references.citation: FEBS J. 2011 Jan;278(1):16-27
references.pmid: 21087457
references.citation: J Cell Mol Med. 2011 May;15(5):1013-31
references.pmid: 21155971
references.citation: Science. 2001 Oct 12;294(5541):339-45
references.pmid: 11546839
references.citation: J Cell Sci. 2010 Nov 1;123(Pt 21):3629-38
references.pmid: 20971702
references.citation: J Mol Biol. 2003 Jul 4;330(2):297-307
references.pmid: 12823969
references.citation: Nature. 2009 Sep 3;461(7260):109-13
references.pmid: 19693011
references.citation: Arch Physiol Biochem. 2006 Jul;112(3):139-49
references.pmid: 17132539
references.citation: Wound Repair Regen. 2006 May-Jun;14(3):313-20
references.pmid: 16808810
references.citation: Science. 2002 Apr 5;296(5565):151-5
references.pmid: 11884718
references.citation: FEBS Lett. 2000 Jun 16;475(2):89-92
references.pmid: 10858494
references.citation: Science. 2009 Sep 4;325(5945):1230-4
references.pmid: 19729652
references.citation: Cell Cycle. 2008 May 1;7(9):1128-32
references.pmid: 18418042
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11175-80
references.pmid: 11572973
references.citation: J Biol Chem. 1999 Sep 3;274(36):25869-76
references.pmid: 10464329
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):2906-11
references.pmid: 14978279
references.citation: Nature. 2006 Apr 27;440(7088):1222-6
references.pmid: 16642001
references.citation: Life Sci. 2002 Nov 15;71(26):3031-45
references.pmid: 12408871
references.citation: Ann Med. 2008;40(6):402-17
references.pmid: 19160570
references.citation: Free Radic Biol Med. 2012 Jan 15;52(2):247-56
references.pmid: 22033009
references.citation: Clin Cancer Res. 2003 Jan;9(1):424-32
references.pmid: 12538496
references.citation: Curr Drug Targets Inflamm Allergy. 2005 Aug;4(4):503-4
references.pmid: 16101529
references.citation: Cell Adh Migr. 2012 May-Jun;6(3):203-19
references.pmid: 22568985
references.citation: Cell Tissue Res. 2010 Jan;339(1):19-29
references.pmid: 19662436
references.citation: Blood. 2008 Dec 15;112(13):4935-9
references.pmid: 18796633
references.citation: J Biol Chem. 2000 Jan 7;275(1):35-40
references.pmid: 10617582
references.citation: J Am Soc Nephrol. 2010 Jan;21(1):93-102
references.pmid: 19926889
references.citation: Nat Rev Mol Cell Biol. 2003 Jun;4(6):479-89
references.pmid: 12778127
references.citation: J Clin Invest. 2003 Dec;112(11):1732-40
references.pmid: 14660749
references.citation: Ann N Y Acad Sci. 1999 Jun 30;878:503-5
references.pmid: 10415755
references.citation: J Cell Biochem. 2010 Feb 15;109(3):447-52
references.pmid: 19950197
references.citation: Biochemistry. 2001 Jul 31;40(30):8861-7
references.pmid: 11467947
references.citation: Genes Dev. 2011 Aug 15;25(16):1716-33
references.pmid: 21852536
references.citation: Science. 2009 Nov 27;326(5957):1216-9
references.pmid: 19965464
references.citation: Acta Med Okayama. 2012;66(5):399-407
references.pmid: 23093058
references.citation: J Invest Dermatol. 2007 Mar;127(3):526-37
references.pmid: 17299435
references.citation: Nat Rev Immunol. 2007 Sep;7(9):678-89
references.pmid: 17717539
references.citation: Antioxid Redox Signal. 2011 Aug 1;15(3):607-19
references.pmid: 21391892
references.citation: J Biol Chem. 2001 Mar 9;276(10):6922-9
references.pmid: 11096074
references.citation: Mol Cell Proteomics. 2007 Sep;6(9):1473-84
references.pmid: 17569890
references.citation: Protein Sci. 2005 Apr;14(4):1091-103
references.pmid: 15772310
references.citation: Anticancer Agents Med Chem. 2010 Dec;10(10):753-68
references.pmid: 21269250
references.citation: J Med Genet. 2005 Sep;42(9):673-85
references.pmid: 16141002
references.citation: Nat Rev Mol Cell Biol. 2002 May;3(5):349-63
references.pmid: 11988769
references.citation: Sci Signal. 2009 Sep 15;2(88):ra53
references.pmid: 19755709
references.citation: Nature. 2010 Nov 25;468(7323):580-4
references.pmid: 21107430
references.citation: Open Biol. 2011 Nov;1(3):110010
references.pmid: 22645650
references.citation: J Biol Chem. 1994 Apr 29;269(17):12395-8
references.pmid: 7909800
references.citation: Chem Biol Drug Des. 2008 Dec;72(6):455-82
references.pmid: 19090915
references.citation: Br J Haematol. 2006 Feb;132(3):339-48
references.pmid: 16409299
references.citation: Biochem J. 1989 Jul 15;261(2):561-8
references.pmid: 2775232
references.citation: J Biol Chem. 2010 Jun 4;285(23):17604-13
references.pmid: 20363746
references.citation: Cold Spring Harb Perspect Biol. 2012 Feb 01;4(2):
references.pmid: 21937733
references.citation: Exp Cell Res. 1995 Dec;221(2):261-71
references.pmid: 7493623
references.citation: Cell. 1996 Jan 12;84(1):155-64
references.pmid: 8548820
references.citation: Mol Genet Metab. 2004 Sep-Oct;83(1-2):16-27
references.pmid: 15464416
references.citation: J Immunol. 2000 Jun 15;164(12):6550-9
references.pmid: 10843714
references.citation: J Cell Biol. 1998 Aug 10;142(3):873-81
references.pmid: 9700173
references.citation: Cold Spring Harb Symp Quant Biol. 2011;76:313-24
references.pmid: 22105806
references.citation: Nat Rev Drug Discov. 2010 Oct;9(10):804-20
references.pmid: 20885411
references.citation: Matrix Biol. 1995 Feb;14(6):439-45
references.pmid: 7795882
references.citation: J Biol Chem. 1997 Nov 7;272(45):28512-7
references.pmid: 9353312
references.citation: J Biol Chem. 2011 Mar 4;286(9):7093-103
references.pmid: 21193390
references.citation: FEBS J. 2012 Apr;279(7):1177-97
references.pmid: 22333131
references.citation: Cardiovasc Ther. 2012 Feb;30(1):e1-8
references.pmid: 20626399
references.citation: J Biol Chem. 2005 Jul 1;280(26):24775-83
references.pmid: 15863495
references.citation: Eur J Immunol. 2003 Mar;33(3):645-55
references.pmid: 12616485
references.citation: Annu Rev Biophys Biomol Struct. 2002;31:485-516
references.pmid: 11988479
references.citation: Oncogene. 2003 Sep 1;22(37):5907-14
references.pmid: 12947397
references.citation: Antioxid Redox Signal. 2010 Aug 15;13(4):467-87
references.pmid: 20001746
references.citation: Nat Med. 2009 Sep;15(9):1077-81
references.pmid: 19701206
references.citation: J Biol Chem. 2006 Sep 1;281(35):25745-56
references.pmid: 16754661
references.citation: Immunol Rev. 2002 Aug;186:141-63
references.pmid: 12234369
references.citation: Thromb Haemost. 2008 Nov;100(5):857-63
references.pmid: 18989530
references.citation: J Pathol. 2003 Jul;200(4):500-3
references.pmid: 12845617
references.citation: PLoS Biol. 2004 Jun;2(6):e153
references.pmid: 15208712
references.citation: Physiol Rev. 2005 Jul;85(3):979-1000
references.pmid: 15987800
references.citation: Am J Physiol Heart Circ Physiol. 2012 Oct 15;303(8):H919-30
references.pmid: 22904159
references.citation: Biochem Soc Trans. 2012 Feb;40(1):129-32
references.pmid: 22260678
references.citation: J Cell Biol. 2012 Apr 2;197(1):131-40
references.pmid: 22451694
references.citation: J Biol Chem. 2008 Jul 11;283(28):19235-44
references.pmid: 18458089
references.citation: Toxicon. 2005 Jun 15;45(8):1063-74
references.pmid: 15922775
references.citation: Proc Natl Acad Sci U S A. 1995 Oct 24;92(22):10277-81
references.pmid: 7479767
references.citation: FEBS J. 2010 Oct;277(19):3864-75
references.pmid: 20840584