Skip to main content
SpringerLink
Log in

Lysyl Oxidase and Lysyl Oxidase-Like Enzymes

  • Chapter
  • First Online:
The Extracellular Matrix: an Overview

Part of the book series: Biology of Extracellular Matrix ((BEM))

Abstract

Lysyl oxidase (LOX) and its four congeners, lysyl oxidase-like 1 (LOXL1), -2, -3, and -4, have received much investigative attention in recent years. LOX itself, is the prototypic form of these amine oxidase enzymes. LOX has long been considered to function exclusively as the enzyme that oxidizes peptidyl lysine in its collagen and elastin substrates, thereby initiating formation of the covalent cross-linkages that stabilize these fibrous proteins. This view has been greatly expanded in light of the revelations that LOX can function both as an anti-oncogenic agent and as an enhancer of malignancy in selected cancerous conditions. Evidence is also accumulating that points to the roles of specific LOXL members of this family in disease and in biological homeostasis. This chapter reviews structural and catalytic properties as well as the roles in biology of these amine oxidases and presents a computer-generated predicted 3D protein structure of LOX.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Akagawa H, Narita A, Yamada H, Tajima A, Krischek B, Kasuya H, Hori T, Kubota M, Saeki N, Hata A, Mizutani T, Inoue I (2007) Systematic screening of lysyl oxidase-like (LOXL) family genes demonstrates that LOXL2 is a susceptibility gene to intracranial aneurysms. Hum Genet 121:377–387

    CAS  PubMed  Google Scholar 

  • Akiri G, Sabo E, Dafni H, Vadasz Z, Kartvelishvily Y, Gan N, Kessler O, Cohen T, Resnick M, Neeman M, Neufeld G (2003) Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo. Cancer Res 63:1657–1666

    CAS  PubMed  Google Scholar 

  • Barrow MV, Steffek AJ (1974) Teratologic and other embryotoxic effects of beta-aminopropionitrile in rats. Teratology 10:165–172

    Google Scholar 

  • Bollinger JA, Brown DE, Dooley DM (2005) The formation of lysine tyrosylquinone (LTQ) is a self-processing reaction. Expression and characterization of a Drosophila lysyl oxidase. Biochemistry 44:11708–11714

    CAS  PubMed  Google Scholar 

  • Bondareva A, Downey CM, Ayres F, Liu W, Boyd SK, Hallgrimsson B, Jirik FR (2009) The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells. PLoS ONE 4:e5620

    PubMed  Google Scholar 

  • Borel A, Eichenberger D, Farjanel J, Kessler E, Gleyzal C, Hulmes DJ, Sommer P, Font B (2001) Lysyl oxidase-like protein from bovine aorta. Isolation and maturation to an active form by bone morphogenetic protein-1. J Biol Chem 276:48944–48949

    CAS  PubMed  Google Scholar 

  • Bouez C, Reynaud C, Noblesse E, Thépot A, Gleyzal C, Kanitakis J, Perrier E, Damour O, Sommer P (2006) The lysyl oxidase LOX is absent in basal and squamous cell carcinomas and its knockdown induces an invading phenotype in a skin equivalent model. Clin Cancer Res 12:1463–1469

    CAS  PubMed  Google Scholar 

  • Brody JS, Kagan HM, Manalo AD, Hu CA, Franzblau C (1976) Lung lysyl oxidase and elastin synthesis during compensatory lung growth. Chest 69:271–272

    CAS  PubMed  Google Scholar 

  • Brown-Augsburger P, Tisdale C, Broekelmann T, Sloan C, Mecham RP (1995) Identification of an elastin cross-linking domain that joins three peptide chains. Possible role in nucleated assembly. J Biol Chem 270:17778–177783

    CAS  PubMed  Google Scholar 

  • Cai D, Klinman JP (1994) Evidence of a self-catalytic mechanism of 2,4,5-trihydroxy-phenylalanine quinone biogenesis in yeast copper amine oxidase. J Biol Chem 269:32039–32042

    CAS  PubMed  Google Scholar 

  • Cairns RA, Khokha R, Hill RP (2003) Molecular mechanisms of tumor invasion and metastasis: an integrated view. Curr Mol Med 3:659–671

    CAS  PubMed  Google Scholar 

  • Choi J, Bergdahl A, Zheng Q, Starcher B, Yanagisawa H, Davis EC (2009) Analysis of dermal elastic fibers in the absence of fibulin-5 reveals potential roles for fibulin-5 in elastic fiber assembly. Matrix Biol 28:211–220

    CAS  PubMed  Google Scholar 

  • Contente S, Kenyon K, Rimoldi D, Friedman RM (1990) Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science 249:796–798

    CAS  PubMed  Google Scholar 

  • Contente S, Yeh TJ, Friedman RM (2009) Tumor suppressive effect of lysyl oxidase proenzyme. Biochim Biophys Acta 1793:1272–1278

    CAS  PubMed  Google Scholar 

  • Cronshaw AD, Fothergill-Gilmore LA, Hulmes DJ (1995) The proteolytic processing site of the precursor of lysyl oxidase. Biochem J 306:279–284

    CAS  PubMed  Google Scholar 

  • Csiszar K (2001) Lysyl oxidases: a novel multifunctional amine oxidase family. Prog Nucleic Acid Res Mol Biol 70:1–32

    CAS  PubMed  Google Scholar 

  • Csiszar K, Fong SF, Ujfalusi A, Krawetz SA, Salvati EP, Mackenzie JW, Boyd CD (2002) Somatic mutations of the lysyl oxidase gene on chromosome 5q23.1 in colorectal tumors. Int J Cancer 97:636–642

    CAS  PubMed  Google Scholar 

  • Di Donato A, Lacal JC, Di Duca M, Giampuzzi M, Ghiggeri G, Gusmana R (1997) Micro-injection of recombinant lysyl oxidase blocks oncogenic p21-Ha-Ras and progesterone effects on Xenopus laevis oocyte maturation. FEBS Lett 419:63–68

    PubMed  Google Scholar 

  • Dubois JL, Klinman JP (2005) Mechanism of post-translational quinone formation in copper amine oxidases and its relationship to the catalytic turnover. Arch Biochem Biophys 433:255–265

    CAS  PubMed  Google Scholar 

  • Erler JT, Bennewith KL, Nicolau M, Dornhöfer N, Kong C, Le QT, Chi JT, Jeffrey SS, Giaccia AJ (2006a) Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440:1222–1226

    CAS  PubMed  Google Scholar 

  • Erler JT, Giaccia AJ (2006b) Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res 66:10238–10241

    CAS  PubMed  Google Scholar 

  • Esteban MA, Tran MG, Harten SK, Hill P, Castellanos MC, Chandra A, Raval R, O’Brien TS, Maxwell PH (2006) Regulation of E-cadherin expression by VHL and hypoxia-inducible factor. Cancer Res 66:3567–3575

    CAS  PubMed  Google Scholar 

  • Evans AJ, Russell RC, Roche O, Burry TN, Fish JE, Chow VW, Kim WY, Saravanan A, Maynard MA, Gervais ML, Sufan RI, Roberts AM, Wilson LA, Betten M, Vandewalle C, Berx G, Marsden PA, Irwin MS, Teh BT, Jewett MA, Ohh M (2007) VHL promotes E2 box-dependent E-cadherin transcription by HIF-mediated regulation of SIP1 and snail. Mol Cell Biol 27:157–169

    CAS  PubMed  Google Scholar 

  • Fernández-Hernando C, József L, Jenkins D, Di Lorenzo A, Sessa WC (2009) Absence of Akt1 reduces vascular smooth muscle cell migration and survival and induces features of plaque vulnerability and cardiac dysfunction during atherosclerosis. Arterioscler Thromb Vasc Biol 29:2033–2040

    PubMed  Google Scholar 

  • Fogelgren B, Polgár N, Szauter KM, Ujfaludi Z, Laczkó R, Fong KS, Csiszar K (2005) Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. J Biol Chem 280:24690–24697

    CAS  PubMed  Google Scholar 

  • Fong SF, Dietzsch E, Fong KS, Hollosi P, Asuncion L, He Q, Parker MI, Csiszar K (2007) Lysyl oxidase-like 2 expression is increased in colon and esophageal tumors and associated with less differentiated colon tumors. Genes Chromosom Cancer 46:644–655

    CAS  PubMed  Google Scholar 

  • Fong SFT, Fong KSK, Csiszar K (2009) LOXL2 (lysyl oxidase-like 2). Atlas Genet Cytogenet Oncol Haematol. http://AtlasGeneticsOncology.org/Genes/LOXL2ID41192ch8p21.html

  • Gacheru SN, Trackman PC, Shah MA, O’Gara CY, Spacciapoli P, Greenaway FT, Kagan HM (1990) Structural and catalytic properties of copper in lysyl oxidase. J Biol Chem 265:19022–19027

    CAS  PubMed  Google Scholar 

  • Giampuzzi M, Oleggini R, Di Donato A (2003) Demonstration of in vitro interaction between tumor suppressor lysyl oxidase and histones H1 and H2: definition of the regions involved. Biochim Biophys Acta 1647:245–251

    CAS  PubMed  Google Scholar 

  • Görögh T, Weise JB, Holtmeier C, Rudolph P, Hedderich J, Gottschlich S, Hoffmann M, Ambrosch P, Csiszar K (2007) Selective upregulation and amplification of the lysyl oxidase like-4 (LOXL4) gene in head and neck squamous cell carcinoma. J Pathol 212:74–82

    PubMed  Google Scholar 

  • Guo Y, Pischon N, Palamakumbura AH, Trackman PC (2007) Intracellular distribution of the lysyl oxidase propeptide in osteoblastic cells. Am J Physiol Cell Physiol 292:C2095–C2102

    CAS  PubMed  Google Scholar 

  • Hämäläinen ER, Kemppainen R, Pihlajaniemi T, Kivirikko KI (1993) Structure of the human lysyl oxidase gene. Genomics 17:544–548

    PubMed  Google Scholar 

  • Hämäläinen ER, Kemppainen R, Kuivaniemi H, Tromp G, Vaheri A, Pihlajaniemi T, Kivirikko KI (1995) Quantitative polymerase chain reaction of lysyl oxidase mRNA in malignantly transformed human cell lines demonstrates that their low lysyl oxidase activity is due to low quantities of its mRNA and low levels of transcription of the respective gene. J Biol Chem 270:21590–21593

    PubMed  Google Scholar 

  • Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Johnson SY, RS KM, Cohen CD, Eckardt KU, Iwano M, Haase VH (2007) Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest 117:3810–3820

    CAS  PubMed  Google Scholar 

  • Hohenester E, Sasaki T, Timpl R (1999) Crystal structure of a scavenger receptor cysteine-rich domain sheds light on an ancient superfamily. Nat Struct Biol 6:228–232

    CAS  PubMed  Google Scholar 

  • Hollosi P, Yakushiji JK, Fong KS, Csiszar K, Fong SF (2009) Lysyl oxidase-like 2 promotes migration in noninvasive breast cancer cells but not in normal breast epithelial cells. Int J Cancer 15:318–327

    Google Scholar 

  • Holtmeier C, Görögh T, Beier U, Meyer J, Hoffmann M, Gottschlich S, Heidorn K, Ambrosch P, Maune S (2003) Overexpression of a novel lysyl oxidase-like gene in human head and neck squamous cell carcinomas. Anticancer Res 23:2585–2591

    CAS  PubMed  Google Scholar 

  • Hornstra IK, Birge S, Starcher B, Bailey AJ, Mecham RP, Shapiro SD (2003) Lysyl oxidase is required for vascular and diaphragmatic development in mice. J Biol Chem 278:14387–14393

    CAS  PubMed  Google Scholar 

  • Hurtado PA, Vora S, Sume SS, Yang D, St. Hilaire C, Guo Y, Palamakumbura AH, Schreiber BM, Ravid K, Trackman PC (2008) Lysyl oxidase propeptide inhibits smooth muscle cell signaling and proliferation. Biochem Biophys Res Commun 366:156–161

    CAS  PubMed  Google Scholar 

  • Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM (2005) MicroRNA gene expression deregulation in human breast cancer. Cancer Res 65:7065–7070

    CAS  PubMed  Google Scholar 

  • Jeay S, Pianetti S, Kagan HM, Sonenshein GE (2003) Lysyl oxidase inhibits ras-mediated transformation by preventing activation of NF-kappa B. Mol Cell Biol 23:2251–2263

    CAS  PubMed  Google Scholar 

  • Jonasson F (2009) From epidemiology to lysyl oxidase like one (LOXL1) polymorphisms discovery: phenotyping and genotyping exfoliation syndrome and exfoliation glaucoma in Iceland. Acta Ophthalmol 87:478–487

    CAS  PubMed  Google Scholar 

  • Jourdan-Le Saux C, Tronecker H, Bogic L, Bryant-Greenwood GD, Boyd CD, Csiszar K (1999) The LOXL2 gene encodes a new lysyl oxidase-like protein and is expressed at high levels in reproductive tissues. J Biol Chem 274:12939–12944

    CAS  PubMed  Google Scholar 

  • Jourdan-Le Saux C, Tomsche A, Ujfalusi A, Jia L, Csiszar K (2001) Central nervous system, uterus, heart, and leukocyte expression of the LOXL3 gene, encoding a novel lysyl oxidase-like protein. Genomics 74:211–218

    CAS  PubMed  Google Scholar 

  • Kagan HM (1986) Characterization and regulation of lysyl oxidase. In: Mecham RP (ed) Biology of the extracellular matrix, vol l, Regulation of matrix accumulation. Academic, Orlando, FL, pp 321–398

    Google Scholar 

  • Kagan HM, Li W (2003) Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. J Cell Biochem 88:660–672

    CAS  PubMed  Google Scholar 

  • Kagan HM, Hewitt NA, Salcedo LL, Franzblau C (1974) Catalytic activity of aortic lysyl oxidase in an insoluble enzyme–substrate complex. Biochim Biophys Acta 365:223–234

    CAS  PubMed  Google Scholar 

  • Kagan HM, Sullivan KA, Olsson TA 3rd, Cronlund AL (1979) Purification and properties of four species of lysyl oxidase from bovine aorta. Biochem J 177:203–214

    CAS  PubMed  Google Scholar 

  • Kagan HM, Raghavan J, Hollander W (1981) Changes in aortic lysyl oxidase activity in diet-induced atherosclerosis in the rabbit. Arteriosclerosis 1:287–291

    CAS  PubMed  Google Scholar 

  • Kagan HM, Williams MA, Calaman SD, Berkowitz EM (1983) Histone H1 is a substrate for lysyl oxidase and contains endogenous sodium borotritide-reducible residues. Biochem Biophys Res Commun 115:186–192

    CAS  PubMed  Google Scholar 

  • Kagan HM, Williams MA, Williamson PR, Anderson JM (1984) Influence of sequence and charge on the specificity of lysyl oxidase toward protein and synthetic peptide substrates. J Biol Chem 259:11203–11207

    CAS  PubMed  Google Scholar 

  • Kaneda A, Wakazono K, Tsukamoto T, Watanabe N, Yagi Y, Tatematsu M, Kaminishi M, Sugimura T, Ushijima T (2004) Lysyl oxidase is a tumor suppressor gene inactivated by methylation and loss of heterozygosity in human gastric cancers. Cancer Res 64:6410–6415

    CAS  PubMed  Google Scholar 

  • Kenyon K, Contente S, Trackman PC, Tang J, Kagan HM, Friedman RM (1991) Lysyl oxidase and rrg messenger RNA. Science 253:802

    CAS  PubMed  Google Scholar 

  • Kenyon K, Modi WS, Contente S, Friedman RM (1993) A novel human cDNA with a predicted protein similar to lysyl oxidase maps to chromosome 15q24–q25. J Biol Chem 268:18435–18437

    Google Scholar 

  • Kessler E, Fichard A, Chanut-Delalande H, Brusel M, Ruggiero F (2001) Bone morphogenetic protein-1 (BMP-1) mediates C-terminal processing of procollagen V homotrimer. J Biol Chem 276:27051–27057

    CAS  PubMed  Google Scholar 

  • Kim M, Okajima T, Kishishita S, Yoshimura M, Kawamori A, Tanizawa K, Yamaguchi H (2002) X-ray snapshots of quinone cofactor biogenesis in bacterial copper amine oxidase. Nat Struct Biol 9:591–596

    CAS  PubMed  Google Scholar 

  • Kim MS, Kim SS, Jung ST, Park JY, Yoo HW, Ko J, Csiszar K, Choi SY, Kim Y (2003) Expression and purification of enzymatically active forms of the human lysyl oxidase-like protein 4. J Biol Chem 278:52071–52074

    Google Scholar 

  • Kim DJ, Lee DC, Yang SJ, Lee JJ, Bae EM, Kim DM, Min SH, Kim SJ, Kang DC, Sang BC, Myung PK, Park KC, Yeom YI (2008) Lysyl oxidase like 4, a novel target gene of TGF-beta1 signaling, can negatively regulate TGF-beta1-induced cell motility in PLC/PRF/5 hepatoma cells. Biochem Biophys Res Commun 373:521–527

    CAS  PubMed  Google Scholar 

  • Kirschmann DA, Seftor EA, Fong SF, Nieva DR, Sullivan CM, Edwards EM, Sommer P, Csiszar K, Hendrix MJ (2002) A molecular role for lysyl oxidase in breast cancer invasion. Cancer Res 62:4478–4483

    CAS  PubMed  Google Scholar 

  • Klutke J, Ji Q, Campeau J, Starcher B, Felix JC, Stanczyk FZ, Klutke C (2008) Decreased endopelvic fascia elastin content in uterine prolapse. Acta Obstet Gynecol Scand 87:111–115

    CAS  PubMed  Google Scholar 

  • Kosonen T, Uriu-Hare JY, Clegg MS, Keen CL, Rucker RB (1997) Incorporation of copper into lysyl oxidase. Biochem J 327:283–289

    CAS  PubMed  Google Scholar 

  • Krieger M, Herz J (1994) Structures and functions of multiligand lipoprotein receptors: macrophage scavenger receptors and LDL receptor-related protein (LRP). Annu Rev Biochem 63:601–637

    CAS  PubMed  Google Scholar 

  • Kuivaniemi H, Korhonen RM, Vaheri A, Kivirikko KI (1986) Deficient production of lysyl oxidase in cultures of malignantly transformed human cells. FEBS Lett 195:261–264

    CAS  PubMed  Google Scholar 

  • Laczko R, Szauter KM, Jansen MK, Hollosi P, Muranyi M, Molnar J, Fong KS, Hinek A, Csiszar K (2007) Active lysyl oxidase (LOX) correlates with focal adhesion kinase (FAK)/paxillin activation and migration in invasive astrocytes. Neuropathol Appl Neurobiol 33:631–643

    CAS  PubMed  Google Scholar 

  • Lazarus HM, Cruikshank WW, Narasimhan N, Kagan HM, Center DM (1995) Induction of human monocyte motility by lysyl oxidase. Matrix Biol 14:727–731

    CAS  PubMed  Google Scholar 

  • Lee J-E, Kim Y (2006) A tissue specific variant of the human lysyl oxidase-like protein 3 (LOXL3) functions as an amine oxidase with substrate specificity. J Biol Chem 281:37282–37290

    CAS  PubMed  Google Scholar 

  • Lee UJ, Gustilo-Ashby AM, Daneshgari F, Kuang M, Vurbic D, Lin DL, Flask CA, Li T, Damaser MS (2008) Lower urogenital tract anatomical and functional phenotype in lysyl oxidase like-1 knockout mice resembles female pelvic floor dysfunction in humans. Am J Physiol Renal Physiol 295:F545–555

    CAS  PubMed  Google Scholar 

  • Lemberg MK, Martoglio B (2002) Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol Cell 10:735–744

    CAS  PubMed  Google Scholar 

  • Li W, Nellaiappan K, Strassmaier T, Graham L, Thomas KM, Kagan HM (1997) Localization and activity of lysyl oxidase within nuclei of fibrogenic cells. Proc Natl Acad Sci USA 94:12817–12822

    CAS  PubMed  Google Scholar 

  • Li W, Liu G, Chou IN, Kagan HM (2000) Hydrogen peroxide-mediated, lysyl oxidase-dependent chemotaxis of vascular smooth muscle cells. J Cell Biochem 78:550–557

    CAS  PubMed  Google Scholar 

  • Li W, Nugent MA, Zhao Y, Chau AN, Li SJ, Chou IN, Liu G, Kagan HM (2003) Lysyl oxidase oxidizes basic fibroblast growth factor and inactivates its mitogenic potential. J Cell Biochem 88:152–164

    CAS  PubMed  Google Scholar 

  • Liu G, Neillaiappan K, Kagan HM (1997) Irreversible inhibition of lysyl oxidase by homocysteine thiolactone and its selenium and oxygen analogues: implications for homocystinuria. J Biol Chem 272:32370–32377

    CAS  PubMed  Google Scholar 

  • Liu X, Zhao Y, Gao J, Pawlyk B, Starcher B, Spencer JA, Yanagisawa H, Zuo J, Li T (2004) Elastic fiber homeostasis requires lysyl oxidase-like 1 protein. Nat Genet 36:178–182

    CAS  PubMed  Google Scholar 

  • López B, Querejeta R, González A, Beaumont J, Larman M, Díez J (2009) Impact of treatment on myocardial lysyl oxidase expression and collagen cross-linking in patients with heart failure. Hypertension 53:236–242

    PubMed  Google Scholar 

  • Lucero HA, Kagan HM (2006) Lysyl oxidase: an oxidative enzyme and effector of cell function. Cell Mol Life Sci 63:2304–2316

    CAS  PubMed  Google Scholar 

  • Lucero HA, Ravid K, Grimsby JL, Rich CB, DiCamillo SJ, Mäki JM, Myllyharju J, Kagan HM (2008) Lysyl oxidase oxidizes cell membrane proteins and enhances the chemotactic response of vascular smooth muscle cells. J Biol Chem 283:24103–24117

    CAS  PubMed  Google Scholar 

  • Mäki JM (2009) Lysyl oxidases in mammalian development and certain pathological conditions. Histol Histopathol 24:651–660

    PubMed  Google Scholar 

  • Mäki J, Kivirikko KI (2001) Cloning and characterization of a fourth human lysyl oxidase isoenzyme. Biochem J 355:381–387

    PubMed  Google Scholar 

  • Mäki JM, Tikkanen H, Kivirikko KI (2001) Cloning and characterization of a fifth human lysyl oxidase isoenzyme: the third member of the lysyl oxidase-related subfamily with four scavenger receptor cysteine-rich domains. Matrix Biol 20:493–496

    PubMed  Google Scholar 

  • Mäki JM, Räsänen J, Tikkanen H, Sormunen R, Mäkikallio K, Kivirikko KI, Soininen R (2002) Inactivation of the lysyl oxidase gene Lox leads to aortic aneurysms, cardiovascular dysfunction, and perinatal death in mice. Circulation 106:2503–2509

    PubMed  Google Scholar 

  • Min C, Kirsch KH, Zhao Y, Jeay S, Palamakumbura AH, Trackman PC, Sonenshein GE (2007) The tumor suppressor activity of the lysyl oxidase propeptide reverses the invasive phenotype of Her-2/neu-driven breast cancer. Cancer Res 67:1105–1112

    CAS  PubMed  Google Scholar 

  • Min C, Yu Z, Kirsch KH, Zhao Y, Vora SR, Trackman PC, Spicer DB, Rosenberg L, Palmer JR, Sonenshein GE (2009) A loss-of-function polymorphism in the propeptide domain of the LOX gene and breast cancer. Cancer Res 69:6685–6693

    CAS  PubMed  Google Scholar 

  • Molnar J, Fong KS, He QP, Hayashi K, Kim Y, Fong SF, Fogelgren B, Szauter KM, Mink M, Csiszar K (2003) Structural and functional diversity of lysyl oxidase and the LOX-like proteins. Biochim Biophys Acta 1647:220–224

    CAS  PubMed  Google Scholar 

  • Mure M (2004) Tyrosine-derived quinone cofactors. Acc Chem Res 37:131–139

    CAS  PubMed  Google Scholar 

  • Nagan N, Kagan HM (1994) Modulation of lysyl oxidase activity toward peptidyl lysine by vicinal dicarboxylic amino acid residues. Implications for collagen cross-linking. J Biol Chem 269:22366–22371

    CAS  PubMed  Google Scholar 

  • Nagan N, Kagan HM (2000) Modulation of lysyl oxidase activity toward peptidyl lysine by vicinal dicarboxylic amino acid residues. Implications for collagen cross-linking. J Biol Chem 269:22366–22371

    Google Scholar 

  • Nellaiappan K, Risitano A, Liu G, Nicklas G, Kagan HM (2000) Fully processed lysyl oxidase catalyst translocates from the extracellular space into nuclei of aortic smooth-muscle cells. J Cell Biochem 79:576–582

    CAS  PubMed  Google Scholar 

  • Ovchinnikova O, Gylfe A, Bailey L, Nordström A, Rudling M, Jung C, Bergström S, Waldenström A, Hansson GK, Nordström P (2009) Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice – brief report. Arterioscler Thromb Vasc Biol 29:1478–1480

    CAS  PubMed  Google Scholar 

  • Palamakumbura AH, Trackman PC (2002) A fluorometric assay for detection of lysyl oxidase enzyme activity in biological samples. Anal Biochem 300:245–2451

    CAS  PubMed  Google Scholar 

  • Palamakumbura AH, Sommer P, Trackman PC (2003) Autocrine growth factor regulation of lysyl oxidase expression in transformed fibroblasts. J Biol Chem 278:30781–30787

    CAS  PubMed  Google Scholar 

  • Palamakumbura AH, Jeay S, Guo Y, Pischon N, Sommer P, Sonenshein GE, Trackman PC (2004) The propeptide domain of lysyl oxidase induces phenotypic reversion of ras-transformed cells. J Biol Chem 279:40593–40600

    CAS  PubMed  Google Scholar 

  • Palamakumbura AH, Vora SR, Nugent MA, Kirsch KH, Sonenshein GE, Trackman PC (2009) Lysyl oxidase propeptide inhibits prostate cancer cell growth by mechanisms that target FGF2 cell binding and signaling. Oncogene 28:3390–3400

    CAS  PubMed  Google Scholar 

  • Panchenko MV, Stetler-Stevenson WG, Trubetskoy OV, Gacheru SN, Kagan HM (1996) Metalloproteinase activity secreted by fibrogenic cells in the processing of prolysyl oxidase. Potential role of procollagen C-proteinase. J Biol Chem 271:7113–7119

    CAS  PubMed  Google Scholar 

  • Pascual G, Mendieta C, Mecham RP, Sommer P, Bellón JM, Buján J (2008) Down-regulation of lysyl oxydase-like in aging and venous insufficiency. Histol Histopathol 23:179–186

    CAS  PubMed  Google Scholar 

  • Payne SL, Fogelgren B, Hess AR, Seftor EA, Wiley EL, Fong SF, Csiszar K, Hendrix MJ, Kirschmann DA (2005) Lysyl oxidase regulates breast cancer cell migration and adhesion through a hydrogen peroxide-mediated mechanism. Cancer Res 65:11429–11436

    CAS  PubMed  Google Scholar 

  • Payne SL, Hendrix MJ, Kirschmann DA (2006) Lysyl oxidase regulates actin filament formation through the p130(Cas)/Crk/DOCK180 signaling complex. J Cell Biochem 98:827–837

    CAS  PubMed  Google Scholar 

  • Payne SL, Hendrix MJ, Kirschmann DA (2007) Paradoxical roles for lysyl oxidases in cancer – a prospect. J Cell Biochem 101:1338–1354

    CAS  PubMed  Google Scholar 

  • Peinado H, Iglesias-de DC, la Cruz M, Olmeda D, Csiszar K, Fong KS, Vega S, Nieto MA, Cano A, Portillo F (2005) A molecular role for lysyl oxidase-like 2 enzyme in snail regulation and tumor progression. EMBO J 24:3446–3458

    CAS  PubMed  Google Scholar 

  • Peng L, Ran YL, Hu H, Yu L, Liu Q, Zhou Z, Sun YM, Sun LC, Pan J, Sun LX, Zhao P, Yang ZH (2009) Secreted LOXL2 is a novel therapeutic target that promotes gastric cancer metastasis via the Src/FAK pathway. Carcinogenesis 30:1660–1669

    CAS  PubMed  Google Scholar 

  • Peyrol S, Raccurt M, Gerard F, Gleyzal C, Grimaud JA, Sommer P (1997) Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma. Am J Pathol 150:497–507

    CAS  PubMed  Google Scholar 

  • Postovit LM, Abbott DE, Payne SL, Wheaton WW, Margaryan NV, Sullivan R, Jansen MK, Csiszar K, Hendrix MJ, Kirschmann DA (2008) Hypoxia/reoxygenation: a dynamic regulator of lysyl oxidase-facilitated breast cancer migration. J Cell Biochem 103:1369–1378

    CAS  PubMed  Google Scholar 

  • Raposo B, Rodríguez C, Martínez-González J, Badimon L (2004) High levels of homocysteine inhibit lysyl oxidase (LOX) and downregulate LOX expression in vascular endothelial cells. Atherosclerosis 177:1–8

    CAS  PubMed  Google Scholar 

  • Ren C, Yang G, Timme TL, Wheeler TM, Thompson TC (1998) Reduced lysyl oxidase messenger RNA levels in experimental and human prostate cancer. Cancer Res 58:1285–1290

    CAS  PubMed  Google Scholar 

  • Rhee SG (2006) Cell signaling. H2O2, a necessary evil for cell signaling. Science 312:1882–1883

    PubMed  Google Scholar 

  • Rodríguez C, Martínez-González J, Raposo B, Alcudia JF, Guadall A, Badimon L (2008) Regulation of lysyl oxidase in vascular cells: lysyl oxidase as a new player in cardiovascular diseases. Cardiovasc Res 79:7–13

    PubMed  Google Scholar 

  • Rodríguez C, Alcudia JF, Martínez-González J, Guadall A, Raposo B, Sánchez-Gómez S, Badimon L (2009) Statins normalize vascular lysyl oxidase down-regulation induced by proatherogenic risk factors. Cardiovasc Res 83:595–603

    PubMed  Google Scholar 

  • Rückert F, Joensson P, Saeger HD, Grützmann R, Pilarsky C (2010) Functional analysis of LOXL2 in pancreatic carcinoma. Int J Colorectal Dis 25:303–311

    PubMed  Google Scholar 

  • Ruggiero CE, Dooley DM (1999) Stoichiometry of the topa quinone biogenesis reaction in copper amine oxidases. Biochemistry 38:2892–2898

    CAS  PubMed  Google Scholar 

  • Russell RC, Ohh M (2007) The role of VHL in the regulation of E-cadherin: a new connection in an old pathway. Cell Cycle 6:56–59

    CAS  PubMed  Google Scholar 

  • Ryvkin F, Greenaway FT (2004) A peptide model of the copper-binding region of lysyl oxidase. J Inorg Biochem 98:1427–1435

    CAS  PubMed  Google Scholar 

  • Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105:6392–6397

    CAS  PubMed  Google Scholar 

  • Saito H, Papaconstantinou J, Sato H, Goldstein S (1997) Regulation of a novel gene encoding a lysyl oxidase-related protein in cellular adhesion and senescence. J Biol Chem 272:8157–8160

    CAS  PubMed  Google Scholar 

  • Schietke RE, Warnecke C, Wacker I, Schodel J, Mole DR, Campean V, Amann K, Goppelt-Struebe M, Behrens J, Eckardt KU, Wiesener MS (2010) The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia – insights into cellular transformation processes mediated by HIF-1. J Biol Chem 285(9):6658–6669

    CAS  PubMed  Google Scholar 

  • Sebban S, Davidson B, Reich R (2009) Lysyl oxidase-like 4 is alternatively spliced in an anatomic site-specific manner in tumors involving the serosal cavities. Virchows Arch 454:71–79

    CAS  PubMed  Google Scholar 

  • Siegel RC (1974) Biosynthesis of collagen crosslinks: increased activity of purified lysyl oxidase with reconstituted collagen fibrils. Proc Natl Acad Sci USA 71:4826–4830

    CAS  PubMed  Google Scholar 

  • Sion AM, Figg WD (2006) Lysyl oxidase (LOX) and hypoxia-induced metastases. Cancer Biol Ther 5:909–911

    CAS  PubMed  Google Scholar 

  • Smith-Mungo LI, Kagan HM (1998) Lysyl oxidase: properties, regulation and multiple functions in biology. Matrix Biol 16:387–398

    CAS  PubMed  Google Scholar 

  • Szauter KM, Csiszar K (2008) LOXL3 (lysyl oxidase-like 3). Atlas Genet Cytogenet Oncol Haematol. http://AtlasGeneticsOncology.org/Genes/LOXL3ID44000ch2p13.html

  • Szauter KM, Gorogh T, Csiszar K (2007) LOXL4 (lysyl oxidase-like 4). Atlas Genet Cytogenet Oncol Haematol. http://AtlasGeneticsOncology.org/Genes/LOXL4ID41193ch10q24.html

  • Tan RS, Taniguchi T, Harada H (1996) Identification of the lysyl oxidase gene as target of the antioncogenic transcription factor, IRF-1, andits possible role in tumor suppression. Cancer Res 56:2417–2421

    CAS  PubMed  Google Scholar 

  • Tang C, Klinman JP (2001) The catalytic function of bovine lysyl oxidase in the absence of copper. J Biol Chem 276:30575–30578

    CAS  PubMed  Google Scholar 

  • Thomassin L, Werneck CC, Broekelmann TJ, Gleyzal C, Hornstra IK, Mecham RP, Sommer P (2005) The pro-regions of lysyl oxidase and lysyl oxidase-like-1 are required for deposition onto elastic fibers. J Biol Chem 280:42848–42855

    CAS  PubMed  Google Scholar 

  • Trackman PC (2005) Diverse biological functions of extracellular collagen processing enzymes. J Cell Biochem 96:927–937

    CAS  PubMed  Google Scholar 

  • Trackman PC, Kagan HM (1979) Nonpeptidyl amine inhibitors are substrates of lysyl oxidase. J Biol Chem 254:7831–7836

    CAS  PubMed  Google Scholar 

  • Trackman PC, Zoski CG, Kagan HM (1981) Development of a peroxidase-coupled fluorometric assay for lysyl oxidase. Anal Biochem 113:336–342

    CAS  PubMed  Google Scholar 

  • Trackman PC, Pratt AM, Wolanski A, Tang SS, Offner GD, Troxler RF, Kagan HM (1990) Cloning of rat aorta lysyl oxidase cDNA: complete codons and predicted amino acid sequence. Biochemistry 29:4863–4870

    CAS  PubMed  Google Scholar 

  • Trackman PC, Pratt AM, Wolanski A, Tang SS, Offner GD, Troxler RF, Kagan HM (1991) Cloning of rat aorta lysyl oxidase cDNA: complete codons and predicted amino acid sequence. Biochemistry 30:8282 (erratum)

    CAS  PubMed  Google Scholar 

  • Trackman PC, Bedell-Hogan D, Tang J, Kagan HM (1992) Post-translational glycosylation and proteolytic processing of a lysyl oxidase precursor. J Biol Chem 267:8666–8671

    CAS  PubMed  Google Scholar 

  • Uzel MI, Scott IC, Babakhanlou-Chase H, Palamakumbura AH, Pappano WN, Hong HH, Greenspan DS, Trackman PC (2001) Multiple bone morphogenetic protein 1-related mammalian met alloproteinases process pro-lysyl oxidase at the correct physiological site and control lysyl oxidase activation in mouse embryo fibroblast cultures. J Biol Chem 276:22537–22543

    CAS  PubMed  Google Scholar 

  • Vadasz Z, Kessler O, Akiri G, Gengrinovitch S, Kagan HM, Baruch Y, Izhak OB, Neufeld G (2005) Abnormal deposition of collagen around hepatocytes in Wilson’s disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol 43:499–507

    CAS  PubMed  Google Scholar 

  • Van der Groep P, Bouter A, Menko FH, van der Wall E, van Diest PJ (2008) High frequency of HIF-1alpha overexpression in BRCA1 related breast cancer. Breast Cancer Res Treat 111:475–480

    CAS  PubMed  Google Scholar 

  • Wang SX, Mure M, Medzihradszky KF, Burlingame AL, Brown DE, Dooley DM, Smith AJ, Kagan HM, Klinman JP (1996) A crosslinked cofactor in lysyl oxidase: redox function for amino acid side chains. Science 273:1078–1084

    CAS  PubMed  Google Scholar 

  • Williams MA, Kagan HM (1985) Assessment of lysyl oxidase variants by urea gel electrophoresis: evidence against disulfide isomers as bases of the enzyme heterogeneity. Anal Biochem 149:430–437

    CAS  PubMed  Google Scholar 

  • Woznick AR, Braddock AL, Dulai M, Seymour ML, Callahan RE, Welsh RJ, Chmielewski GW, Zelenock GB, Shanley CJ (2005) Lysyl oxidase expression in bronchogenic carcinoma. Am J Surg 189:297–301

    CAS  PubMed  Google Scholar 

  • Wu G, Guo Z, Chang X, Kim MS, Nagpal JK, Liu J, Maki JM, Kivirikko KI, Ethier SP, Trink B, Sidransky D (2007a) LOXL1 and LOXL4 are epigenetically silenced and can inhibit ras/extracellular signal-regulated kinase signaling pathway in human bladder cancer. Cancer Res 67:4123–4129

    CAS  PubMed  Google Scholar 

  • Wu M, Min C, Wang X, Yu Z, Kirsch KH, Trackman PC, Sonenshein GE (2007b) Repression of BCL2 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells. Cancer Res 67:6278–6285

    CAS  PubMed  Google Scholar 

  • Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, Calin GA, Liu CG, Croce CM, Harris CC (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198

    CAS  PubMed  Google Scholar 

  • Zhao Y, Min C, Vora SR, Trackman PC, Sonenshein GE, Kirsch KH (2009) The Lysyl oxidase propeptide attenuates fibronectin-mediated activation of focal adhesion kinase and p130Cas in breast cancer cells. J Biol Chem 284:1385–1393

    CAS  PubMed  Google Scholar 

  • Zia MK, Rmali KA, Watkins G, Mansel RE, Jiang WG (2007) The expression of the von Hippel-Lindau gene product and its impact on invasiveness of human breast cancer cells. Int J Mol Med 20:605–611

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry, Boston University School of Medicine, 715 Albany Street, Boston, MA, 02118, USA

    Herbert M. Kagan

  2. Emmanuel College, 400 The Fenway, Boston, MA, 02115, USA

    Faina Ryvkin

Authors
  1. Herbert M. Kagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Faina Ryvkin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Herbert M. Kagan .

Editor information

Editors and Affiliations

  1. School of Medicine, Dept. Cell Biology & Physiology, Washington University, S. Euclid Avenue 660, St. Louis, 63110, Missouri, USA

    Robert P. Mecham

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Berlin Heidelberg

About this chapter

Cite this chapter

Kagan, H.M., Ryvkin, F. (2011). Lysyl Oxidase and Lysyl Oxidase-Like Enzymes. In: Mecham, R. (eds) The Extracellular Matrix: an Overview. Biology of Extracellular Matrix. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-16555-9_9

Download citation

Publish with us

Policies and ethics

Search

Navigation