586
Views
46
CrossRef citations to date
0
Altmetric
Review Article

The role of perlecan and endorepellin in the control of tumor angiogenesis and endothelial cell autophagy

, &
Pages 381-391 | Received 09 Mar 2015, Accepted 16 Apr 2015, Published online: 16 Jul 2015

References

  • Iozzo RV. Basement membrane proteoglycans: from cellar to ceiling. Nat Rev Mol Cell Biol 2005;6:646–56
  • Farach-Carson MC, Carson DD. Perlecan – a multifunctional extracellular proteoglycan scaffold. Glycobiology 2007;17:897–905
  • Wilusz RE, Sanchez-Adams J, Guilak F. The structure and function of the pericellular matrix of articular cartilage. Matrix Biol 2014;39:25–32
  • Abedin M, King N. Diverse evolutionary paths to cell adhesion. Trends Cell Biol 2010;20:734–42
  • Iozzo RV, Murdoch AD. Proteoglycans of the extracellular environment: clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J 1996;10:598–614
  • Iozzo RV, Schaefer L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol 2015;42:11–55
  • Iozzo RV, Schaefer L. Proteoglycans in health and disease: novel regulatory signaling mechanisms evoked by the small leucine-rich proteoglycans. FEBS J 2010;277:3864–75
  • Iozzo RV. Matrix proteoglycans: from molecular design to cellular function. Annu Rev Biochem 1998;67:609–52
  • Iozzo RV, Cohen IR, Grässel S, Murdoch AD. The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem J 1994;302:625–39
  • Hassell JR, Robey PG, Barrach HJ, Wilczek J, Rennard SI, Martin GR. Isolation of a heparan sulfate-containing proteoglycan from basement membrane. Proc Natl Acad Sci USA 1980;77:4494–8
  • Murdoch AD, Dodge GR, Cohen I, Tuan RS, Iozzo RV. Primary structure of the human heparan sulfate proteoglycan from basement membrane (HSPG2/perlecan). A chimeric molecule with multiple domains homologous to the low density lipoprotein receptor, laminin, neural cell adhesion molecules, and epidermal growth factor. J Biol Chem 1992;267:8544–57
  • Iozzo RV, Hassell JR. Identification of the precursor protein for the heparan sulfate proteoglycan of human colon carcinoma cells and its post-translational modifications. Arch Biochem Biophys 1989;269:239–49
  • Dodge GR, Kovalszky I, Chu M-L, Hassell J R, McBride OW, Yi HF, Iozzo RV. Heparan sulfate proteoglycan of human colon: partial molecular cloning, cellular expression, and mapping of the gene (HSPG2) to the short arm of human chromosome 1. Genomics 1991;10:673–80
  • Cohen IR, Grässel S, Murdoch AD, Iozzo RV. Structural characterization of the complete human perlecan gene and its promoter. Proc Natl Acad Sci USA 1993;90:10404–8
  • Iozzo RV, Pillarisetti J, Sharma B, Murdoch AD, Danielson KG, Uitto J, Mauviel A. Structural and functional characterization of the human perlecan gene promoter. Transcriptional activation by transforming factor-β via a nuclear factor 1-binding element. J Biol Chem 1997;272:5219–28
  • Iozzo RV, Danielson KG. Transcriptional and post-transcriptional control of proteoglycan gene expression. Progr Nucl Acids Res Mol Biol 1999;62:19–53
  • Sharma B, Iozzo RV. Transcriptional silencing of perlecan gene expression by interferon-γ. J Biol Chem 1998;273:4642–6
  • Dodge GR, Kovalszky I, Hassell JR, Iozzo RV. Transforming growth factor β alters the expression of heparan sulfate proteoglycan in human colon carcinoma cells. J Biol Chem 1990;265:18023–9
  • Grässel S, Cohen IR, Murdoch AD, Eichstetter I, Iozzo RV. The proteoglycan perlecan is expressed in the erythroleukemia cell line K562 and is upregulated by sodium butyrate and phorbol ester. Mol Cell Biochem 1995;145:61–8
  • Jung M, Lord MS, Cheng B, Lyons JG, Alkhouri H, Hughes JM, McCarthy SJ, Iozzo RV, Whitelock JM. Mast cells produce novel shorter forms of perlecan that contain functional endorepellin: a role in angiogenesis and wound healing. J Biol Chem 2013;288:3289–304
  • Lord MS, Jung M, Cheng B, Whitelock JM. Transcriptional complexity of the HSPG2 gene in the human mast cell line, HMC-1. Matrix Biol 2014;35:123–31
  • Handler M, Yurchenco PD, Iozzo RV. Developmental expression of perlecan during murine embryogenesis. Dev Dyn 1997;210:130–45
  • Arikawa-Hirasawa E, Watanabe E, Takami H, Hassell JR, Yamada Y. Perlecan is essential for cartilage and cephalic development. Nat Genet 1999;23:354–8
  • Costell M, Gustafsson E, Aszódi A, Mörgelin M, Bloch W, Hunziker E, Addicks K, Timpl R, Fässler R. Perlecan maintains the integrity of cartilage and some basement membranes. J Cell Biol 1999;147:1109–22
  • Arikawa-Hirasawa E, Wilcox WR, Le AH, Silverman N, Govindraj P, Hassell JR, Yamada Y. Dyssegmental dysplasia, Silverman–Handmaker type, is caused by functional null mutations of the perlecan gene. Nat Genet 2001;27:431–4
  • Henriquez JP, Casar JC, Fuentealba L, Carey DJ, Brandan E. Extracellular matrix histone H1 binds to perlecan, is present in regenerating skeletal muscle and stimulates myoblast proliferation. J Cell Sci 2002;115:2041–51
  • Nicole S, Davoine C-S, Topaloglu H, Cattolico L, Barral D, Beighton P, Hamida CB, Hammouda H, Cruaud C, White PS, Samson D, Urtizberea JA, Lehmann-Horn F, Weissenbach J, Hentati F, Fontaine B. Perlecan, the major proteoglycan of basement membranes, is altered in patients with Schwartz–Jampel syndrome (chondrodystrophic myotonia). Nat Genet 2000;26:480–3
  • Arikawa-Hirasawa E, Le AH, Nishino I, Nonaka I, Ho NC, Francomano CA, Govindraj P, Hassell JR, Devaney JM, Spranger J, Stevenson RE, Iannaccone S, Dalakas MC, Yamada Y. Structural and functional mutations of the perlecan gene cause Schwartz–Jampel syndrome, with myotonic myopathy and chondrodysplasia. Am J Hum Genet 2002;70:1368–75
  • Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, Superti-Furga A. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A 2011;155A:943–68
  • Echaniz-Laguna A, Rene F, Marcel C, Bangratz M, Fontaine B, Loeffler J-P, Nicole S. Electrophysiological studies in a mouse model of Schwartz–Jampel syndrome demonstrate muscle fiber hyperactivity of peripheral nerve origin. Muscle Nerve 2009;40:55–61
  • Lowe DA, Lepori-Bui N, Fomin PV, Sloofman LG, Zhou X, Farach-Carson MC, Wang L, Kirn-Safran CB. Deficiency in perlecan/HSPG2 during bone development enhances osteogenesis and decreases quality of adult bone in mice. Calcif Tissue Int 2014;95:29–38
  • Rodgers KD, Sasaki T, Aszodi A, Jacenko O. Reduced perlecan in mice results in chondrodysplasia resembling Schwartz–Jampel syndrome. Hum Mol Gen 2007;16:515–28
  • Sasse P, Malan P, Fleischmann M, Roell W, Gustafsson E, Bostani T, Fan Y, Kolbe T, Breitbach M, Addicks K, Welz A, Brem G, Hescheler J, Aszodi A, Costell M, Bloch W, Fleischmann BK. Perlecan is critical for heart stability. Cardiovasc Res 2008;80:435–44
  • Iozzo RV, San Antonio JD. Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J Clin Invest 2001;108:349–55
  • Iozzo RV, Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med 2011;15:1013–31
  • Willis CD, Schaefer L, Iozzo RV. The biology of perlecan and its bioactive modules. In Karamanos NK, ed. Extracellular matrix: pathobiology and signaling. Berlin: Walter de Gruyter GmbH & Co. KG; 2012:171–84
  • Carson DD, Tang J-P, Julian J. Heparan sulfate proteoglycan (perlecan) expression by mouse embryos during acquisition of attachment competence. Dev Biol 1993;155:97–106
  • Iozzo RV. Biosynthesis of heparan sulfate proteoglycan by human colon carcinoma cells and its localization at the cell surface. J Cell Biol 1984;99:403–17
  • Murdoch AD, Liu B, Schwarting R, Tuan RS, Iozzo RV. Widespread expression of perlecan proteoglycan in basement membranes and extracellular matrices of human tissues as detected by a novel monoclonal antibody against domain III and by in situ hybridization. J Histochem Cytochem 1994;42:239–49
  • Zoeller JJ, McQuillan A, Whitelock J, Ho S-Y, Iozzo RV. A central function for perlecan in skeletal muscle and cardiovascular development. J Cell Biol 2008;181:381–94
  • Whitelock JM, Graham LD, Melrose J, Murdoch AD, Iozzo RV, Underwood PA. Human perlecan immunopurified from different endothelial cell sources has different adhesive properties for vascular cells. Matrix Biol 1999;18:163–78
  • Farach-Carson MC, Brown AC, Lynam M, Safran JB, Carson DD. A novel peptide sequence in perlecan domain IV supports cell adhesion, spreading and FAK activation. Matrix Biol 2008;27:150–60
  • Farach-Carson MC, Warren CR, Harrington DA, Carson DD. Border patrol: insights into the unique role of perlecan/heparan sulfate proteoglycan 2 at cell and tissue borders. Matrix Biol 2014;34:64–79
  • Lord MS, Chuang CY, Melrose J, Davies MJ, Iozzo RV, Whitelock JM. The role of vascular-derived perlecan in modulating cell adhesion, proliferation and growth factor signaling. Matrix Biol 2014;35:112–22
  • Grindel BJ, Martinez JR, Pennington CL, Muldoon M, Stave J, Chung LW, Farach-Carson MC. Matrilysin/matrix metalloproteinase-7(MMP7) cleavage of perlecan/HSPG2 creates a molecular switch to alter prostate cancer cell behavior. Matrix Biol 2014;36:64–76
  • Gotha L, Lim SY, Osherov AB, Wolff R, Qiang B, Erlich I, Nili N, Pillarisetti S, Chang YT, Tran PK, Tryggvason K, Hedin U, Tran-Lundmark K, Advani SL, Gilbert RE, Strauss BH. Heparan sulfate side chains have a critical role in the inhibitory effects of perlecan on vascular smooth muscle cell response to arterial injury. Am J Physiol Heart Circ Physiol 2014;307:H337–45
  • Tran P-K, Tran-Lundmark K, Soininen R, Tryggvason K, Thyberg J, Hedin U. Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ Res 2004;94:550–8
  • Nugent MA, Nugent HM, Iozzo RV, Sanchack K, Edelman ER. Perlecan is required to inhibit thrombosis after deep vascular injury and contributes to endothelial cell-mediated inhibition of intimal hyperplasia. Proc Natl Acad Sci USA 2000;97:6722–7
  • Iozzo RV. Turnover of heparan sulfate proteoglycan in human colon carcinoma cells. A quantitative biochemical and autoradiographic study. J Biol Chem 1987;262:1888–900
  • Fuki I, Iozzo RV, Williams KJ. Perlecan heparan sulfate proteoglycan: a novel receptor that mediates a distinct pathway for ligand catabolism. J Biol Chem 2000;275:25742–50
  • Xu Y, Ashline D, Liu L, Tassa C, Shaw SY, Ravid K, Layne MD, Reinhold V, Robbins PW. The glycosylation-dependent interaction of perlecan core protein with LDL: implications for atherosclerosis. J Lipid Res 2015;56:266–76
  • Inomata T, Ebihara N, Funaki T, Matsuda A, Wantanabe Y, Ning L, Xu Z, Murakami A, Arikawa-Hirasawa E. Perlecan-deficient mutation impairs corneal epithelial structure. Invest Ophtalmol Vis Sci 2012;53:1277–84
  • Sher I, Zisman-Rozen S, Eliahu L, Whitelock JM, Maas-Szabowski N, Yamada Y, Breitkreutz D, Fusenig N E, Arikawa-Hirasawa E, Iozzo RV, Bergman R, Ron D. Targeting perlecan in human keratinocytes reveals novel roles for perlecan in epidermal formation. J Biol Chem 2006;281:5178–87
  • Kaneko H, Ishijima M, Futami I, Tomikawa-Ichikawa N, Kosaki K, Sadatsuki R, Yamada Y, Kurosawa H, Kaneko K, Arikawa-Hirasawa E. Synovial perlecan is required for osteophyte formation in knee osteoarthritis. Matrix Biol 2013;32:178–87
  • SundarRaj N, Fite D, Ledbetter S, Chakravarti S, Hassell JR. Perlecan is a component of cartilage matrix and promotes chondrocyte attachment. J Cell Sci 1995;108:2663–72
  • Jochmann K, Bachvarova V, Vortkamp A. Reprint of: heparan sulfate as a regulator of endochondral ossification and osteochondroma development. Matrix Biol 2014;35:239–47
  • Laplante P, Raymond M-A, Labelle A, Abe J-I, Iozzo RV, Hebért M-J. Perlecan proteolysis induces α2β1 integrin and src-family kinases dependent anti-apoptotic pathway in fibroblasts in the absence of focal adhesion kinase activation. J Biol Chem 2006;281:30383–92
  • Rossi M, Morita H, Sormunen R, Airenne S, Kreivi M, Wang L, Fukai N, Olsen BR, Tryggvason K, Soininen R. Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J 2003;22:236–45
  • Arikawa-Hirasawa E, Rossi SG, Rotundo RL, Yamada Y. Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice. Nat Neurosci 2002;5:119–23
  • Colombelli C, Palmisano M, Eshed-Eisenbach Y, Zambroni D, Pavoni E, Ferri C, Saccucci S, Nicole S, Soininen R, McKee KK, Yurchenco PD, Peles E, Wrabetz L, Feltri ML. Perlecan is recruited by dystroglycan to nodes of Ranvier and binds the clustering molecule gliomedin. J Cell Biol 2015;208:313–29
  • Aviezer D, Hecht D, Safran M, Eisinger M, David G, Yayon A. Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis, and angiogenesis. Cell 1994;79:1005–13
  • Aviezer D, Iozzo RV, Noonan DM, Yayon A. Suppression of autocrine and paracrine functions of basic fibroblast growth factor by stable expression of perlecan antisense cDNA. Mol Cell Biol 1997;17:1938–46
  • Segev A, Nili N, Strauss BH. The role of perlecan in arterial injury and angiogenesis. Cardiovasc Res 2004;63:603–10
  • Zoeller JJ, Whitelock J, Iozzo RV. Perlecan regulates developmental angiogenesis by modulating the VEGF-VEGFR2 axis. Matrix Biol 2009;28:284–91
  • Whitelock JM, Iozzo RV. Heparan sulfate: a complex polymer charged with biological activity. Chem Rev 2005;105:2745–64
  • Mathiak M, Yenisey C, Grant DS, Sharma B, Iozzo RV. A role for perlecan in the suppression of growth and invasion in fibrosarcoma cells. Cancer Res 1997;57:2130–6
  • Sharma B, Handler M, Eichstetter I, Whitelock J, Nugent MA, Iozzo RV. Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo. J Clin Invest 1998;102:1599–608
  • Jiang X, Couchman JR. Perlecan and tumor angiogenesis. J Histochem Cytochem 2003;51:1393–410
  • Bix G, Iozzo RV. Novel interactions of perlecan: unraveling perlecan's role in angiogenesis. Microsc Res 2008;71:339–48
  • Jiang J, Multhaupt H, Chan E, Schaefer L, Schaefer RM, Couchman JR. Essential contribution of tumor-derived perlecan to epidermal tumor growth and angiogenesis. J Histochem Cytochem 2004;52:1575–90
  • Qiang B, Lim SY, Lekas M, Kuliszewski MA, Wolff R, Osherov AB, Rudenko D, Leong-Poi H, Noyan H, Husain M, Tran K, Tryggvason K, Hedin U, Tran-Lundmark K, Strauss BH. Perlecan heparan sulfate proteoglycan is a critical determinant of angiogenesis in response to mouse hind-limb ischemia. Can J Cardiol 2014;30:1444–51
  • Ghiselli G, Eichstetter I, Iozzo RV. A role for the perlecan protein core in the activation of the keratinocyte growth factor receptor. Biochem J 2001;359:153–63
  • Smith SML, West LA, Hassell JR. The core protein of growth plate perlecan binds FGF-18 and alters its mitogenic effect on chondrocytes. Arch Biochem Biophys 2007;468:244–51
  • Vincent TL, McLean CJ, Full LE, Peston D, Saklatvala J. FGF-2 is bound to perlecan in the pericellular matrix of articular cartilage, where it acts as a chondrocyte mechanotransducer. Osteoarthritis Cartilage 2007;15:752–63
  • Ishijima M, Suzuki N, Hozumi K, Matsunobu T, Kosaki K, Kaneko H, Hassell JR, Arikawa-Hirasawa E, Yamada Y. Perlecan modulates VEGF signaling and is essential for vascularization in endochondral bone formation. Matrix Biol 2012;31:234–45
  • Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown A, Iozzo RV. Perlecan protein core interacts with extracellular matrix protein 1 (ECM1), a glycoprotein involved in bone formation and angiogenesis. J Biol Chem 2003;278:17491–9
  • Mongiat M, Taylor K, Otto J, Aho S, Uitto J, Whitelock J, Iozzo RV. The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7. J Biol Chem 2000;275:7095–100
  • Mongiat M, Otto J, Oldershaw R, Ferrer F, Sato JD, Iozzo RV. Fibroblast growth factor-binding protein is a novel partner for perlecan protein core. J Biol Chem 2001;276:10263–71
  • Gonzalez EM, Mongiat M, Slater SJ, Baffa R, Iozzo RV. A novel interaction between perlecan protein core and progranulin: potential effects on tumor growth. J Biol Chem 2003;278:38113–16
  • Monami G, Gonzalez EM, Hellman M, Gomella LG, Baffa R, Iozzo RV, Morrione A. Proepithelin promotes migration and invasion of 5637 bladder cancer cells through the activation of ERK 1/2 and the formation of a paxillin/FAK/ERK complex. Cancer Res 2006;66:7103–10
  • Monami G, Emiliozzi V, Bitto A, Lovat F, Xu S-Q, Goldoni S, Fassan M, Serrero G, Gomella LG, Baffa R, Iozzo RV, Morrione A. Proepithelin regulates prostate cancer cell biology by promoting cell growth, migration, and anchorage-independent growth. Am J Pathol 2009;174:1037–47
  • Iozzo RV, Zoeller JJ, Nyström A. Basement membrane proteoglycans: modulators par excellence of cancer growth and angiogenesis. Mol Cells 2009;27:503–13
  • Gustafsson E, Almonte-Becerril M, Bloch W, Costell M. Perlecan maintains microvessel integrity in vivo and modulates their formation in vitro. PLoS ONE 2013;8:e53715
  • Zhou Z, Wang J, Cao R, Morita H, Soininen R, Chan KM, Liu B, Cao Y, Tryggvason K. Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res 2004;64:4699–702
  • Nonaka R, Iesaki T, de VS, Daida H, Okada T, Sasaki T, Arikawa-Hirasawa E. Perlecan deficiency causes endothelial dysfunction by reducing the expression of endothelial nitric oxide synthase. Physiol Rep 2015;3:e12272
  • Whitelock JM, Murdoch AD, Iozzo RV, Underwood PA. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin and heparanases. J Biol Chem 1996;271:10079–86
  • Reiland J, Sanderson RD, Waguespack M, Barker SA, Long R, Carson DD, Marchetti D. Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. J Biol Chem 2004;279:8047–55
  • Sanderson RD, Iozzo RV. Targeting heparanase for cancer therapy at the tumor–matrix interface. Matrix Biol 2012;31:283–4
  • Peysselon F, Ricard-Blum S. Heparin–protein interactions: from affinity and kinetics to biological roles. Application to an interaction network regulating angiogenesis. Matrix Biol 2014;35:73–81
  • Vlodavsky I, Iozzo RV, Sanderson RD. Heparanase: multiple functions in inflammation, diabetes and atherosclerosis. Matrix Biol 2013;32:220–2
  • Vlodavsky I, Blich M, Li JP, Sanderson RD, Ilan N. Involvement of heparanase in atherosclerosis and other vessel wall pathologies. Matrix Biol 2013;32:241–51
  • Peterson SB, Liu J. Multi-faceted substrate specificity of heparanase. Matrix Biol 2013;32:223–7
  • Goldberg R, Meirovitz A, Hirshoren N, Bulvik R, Binder A, Rubinstein AM, Elkin M. Versatile role of heparanase in inflammation. Matrix Biol 2013;32:234–40
  • Parish CR, Freeman C, Ziolkowski AF, He YQ, Sutcliffe EL, Zafar A, Rao S, Simeonovic CJ. Unexpected new roles for heparanase in Type 1 diabetes and immune gene regulation. Matrix Biol 2013;32:228–33
  • Cohen IR, Murdoch AD, Naso MF, Marchetti D, Berd D, Iozzo RV. Abnormal expression of perlecan proteoglycan in metastatic melanomas. Cancer Res 1994;54:5771–4
  • Iozzo RV, Cohen I. Altered proteoglycan gene expression and the tumor stroma. Experientia 1993;49:447–55
  • Davies EJ, Backhall FH, Shanks JH, David G, McGown AT, Swindell R, Slade RJ, Martin-Hirsch P, Gallagher JT, Jayson GC. Distribution and clinical significance of heparan sulfate proteoblycans in ovarian cancer. Clin Cancer Res 2004;10:5178–86
  • Kawahara R, Granato DC, Carnielli CM, Cervigne NK, Oliveria CE, Martinez CA, Yokoo S, Fonseca FP, Lopes M, Santos-Silva AR, Graner E, Coletta RD, Paes Leme AF. Agrin and perlecan mediate tumorigenic processes in oral squamous cell carcinoma. PLoS One 2014;9:e115004
  • Duncan MB. Extracellular matrix transcriptome dynamics in hepatocellular carcinoma. Matrix Biol 2013;32:393–8
  • Savoré C, Zhang C, Muir C, Liu R, Wyrwa J, Shu J, Zhau HE, Chung LW, Carson DD, Farach-Carson MC. Perlecan knockdown in metastatic prostate cancer cells reduces heparin-binding growth factor responses in vitro and tumor growth in vivo. Clin Exp Metastasis 2005;22:377–90
  • Warren CR, Grindel BJ, Francis L, Carson DD, Farach-Carson MC. Transcriptional activation by NFkappaB increases perlecan/HSPG2 expression in the desmoplastic prostate tumor microenvironment. J Cell Biochem 2014;115:1322–33
  • Mongiat M, Sweeney S, San Antonio JD, Fu J, Iozzo RV. Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J Biol Chem 2003;278:4238–49
  • Le BV, Kim H, Choi J, Kim J-H, Hahn M-J, Lee C, Kim KK, Hwang H-Y. Crystal structure of the LG3 domain of endorepellin, an angiogenesis inhibitor. J Mol Biol 2011;414:231–42
  • Cailhier J-F, Sirois I, Raymond M-A, Lepage S, Laplante P, Brassard N, Prat A, Iozzo RV, Pshezhetsky AV, Hebért M-J. Caspase-3 activation triggers extracellular release of cathepsin L and endorepellin proteolysis. J Biol Chem 2008;283:27220–9
  • Gonzalez EM, Reed CC, Bix G, Fu J, Zhang Y, Gopalakrishnan B, Greenspan DS, Iozzo RV. BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J Biol Chem 2005;280:7080–7
  • O'Riordan E, Orlova TN, Mendelev N, Patschan D, Kemp R, Chander PN, Hu R, Hao G, Gross SS, Iozzo RV, Delaney V, Goligorsky MS. Urinary proteomic analysis of chronic renal allograft nephropathy. Proteomics Clin Appl 2008;2:1025–35
  • Wang H, Listrat A, Meunier B, Gueugneau M, Coudy-Gandilhon C, Combaret L, Taillandier D, Polge C, Attaix D, Lethias C, Lee K, Goh KL, Bechet D. Apoptosis in capillary endothelial cells in ageing skeletal muscle. Aging Cell 2014;13:254–62
  • Whitelock JM, Melrose J, Iozzo RV. Diverse cell signaling events modulated by perlecan. Biochemistry 2008;47:11174–83
  • Lindner JR, Hillman PR, Barrett AL, Jackson MC, Perry TL, Park Y, Datta S. The Drosophila Perlecan gene trol regulates multiple signaling pathways in different developmental contexts. BMC Dev Biol 2007;7:121
  • Trisnadi N, Stathopoulos A. Ectopic expression screen identifies genes affecting drosophila mesoderm development including the HSPG trol. G3 (Bethesda) 2014;5:301–13
  • Datta MW, Hernandez AM, Schlicht MJ, Kahler AJ, DeGueme AM, Dhir R, Shah RB, Farach-Carson C, Barrett A, Datta S. Perlecan, a candidate gene for the CAPB locus, regulates prostate cancer cell growth via the Sonic Hedgehog pathway. Mol Cancer 2006;5:9
  • Datta S, Pierce M, Datta MW. Perlecan signaling: helping hedgehog stimulate prostate cancer growth. Int J Biochem Cell Biol 2006;38:1855–61
  • Goyal A, Poluzzi C, Willis AC, Smythies J, Shellard A, Neill T, Iozzo RV. Endorepellin affects angiogenesis by antagonizing diverse VEGFR2-evoked signaling pathways: transcriptional repression of HIF-1α and VEGFA and concurrent inhibition of NFAT1 activation. J Biol Chem 2012;287:43543–56
  • Goyal A, Pal N, Concannon M, Paulk M, Doran M, Poluzzi C, Sekiguchi K, Whitelock JM, Neill T, Iozzo RV. Endorepellin, the angiostatic module of perlecan, interacts with both the α2β1 integrin and vascular endothelial growth factor receptor 2 (VEGFR2). J Biol Chem 2011;286:25947–62
  • Bix G, Fu J, Gonzalez E, Macro L, Barker A, Campbell S, Zutter MM, Santoro SA, Kim JK, Höök M, Reed CC, Iozzo RV. Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through the α2β1 integrin. J Cell Biol 2004;166:97–109
  • Bix G, Castello R, Burrows M, Zoeller JJ, Weech M, Iozzo RA, Cardi C, Thakur MT, Barker CA, Camphausen KC, Iozzo RV. Endorepellin in vivo: targeting the tumor vasculature and retarding cancer growth and metabolism. J Natl Cancer Inst 2006;98:1634–46
  • Bix G, Iozzo RA, Woodall B, Burrows M, McQuillan A, Campbell S, Fields GB, Iozzo RV. Endorepellin, the C-terminal angiostatic module of perlecan, enhances collagen-platelet responses via the α2β1 integrin receptor. Blood 2007;109:3745–8
  • Bix G, Iozzo RV. Matrix revolutions: “tails” of basement-membrane components with angiostatic functions. Trends Cell Biol 2005;15:52–60
  • Nyström A, Shaik ZP, Gullberg D, Krieg T, Eckes B, Zent R, Pozzi A, Iozzo RV. Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity. Blood 2009;114:4897–906
  • Zoeller JJ, Iozzo RV. Proteomic profiling of endorepellin angiostatic activity on human endothelial cells. Proteome Sci 2008;6:7
  • Senger DR, Claffey KP, Benes JE, Perruzzi CA, Sergiou AP, Detmar M. Angiogenesis promoted by vascular endothelial growth factor: regulation through α1β1 and α2β1 integrins. Proc Natl Acad Sci USA 1997;94:13612–17
  • Sweeney SM, DiLullo G, Slater SJ, Martinez J, Iozzo RV, Lauer-Fields JL, Fields GB, San Antonio JD. Angiogenesis in collagen I requires α2β1 ligation of a GFP*GER sequence and possible p38 MAPK activation and focal adhesion disassembly. J Biol Chem 2003;278:30516–24
  • San Antonio JD, Zoeller J J, Habursky K, Turner K, Pimtong W, Burrows M, Choi S, Basra S, Bennett JS, DeGrado WF, Iozzo RV. A key role for the integrin α2β1 in experimental and developmental angiogenesis. Am J Pathol 2009;175:1338–47
  • Woodall BP, Nyström A, Iozzo RA, Eble JA, Niland S, Krieg T, Eckes B, Pozzi A, Iozzo R V. Integrin α2β1 is the required receptor for endorepellin angiostatic activity. J Biol Chem 2008;283:2335–43
  • Willis CD, Poluzzi C, Mongiat M, Iozzo RV. Endorepellin laminin-like globular repeat 1/2 domains bind Ig3-5 of vascular endothelial growth factor (VEGF) receptor 2 and block pro-angiogenic signaling by VEGFA in endothelial cells. FEBS J 2013;280:2271–94
  • Poluzzi C, Casulli J, Goyal A, Mercer TJ, Neill T, Iozzo RV. Endorepellin evokes autophagy in endothelial cells. J Biol Chem 2014;289:16114–28
  • Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004;15:1101–11
  • He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009;43:67–93
  • Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, Mukherjee C, Shi Y, Gelinas C, Fan Y, Nelson DA, Jin S, White E. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10:51–64
  • Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T. ER stress (PERK/eIF2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 2007;14:230–9
  • Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, Thompson CB. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell 2005;120:237–48
  • Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, Jimenez-Sanchez M, Korolchuk VI, Lichtenberg M, Luo S, Massey DC, Menzies FM, Moreau K, Narayanan U, Renna M, Siddiqi FH, Underwood BR, Winslow AR, Rubinsztein DC. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010;90:1383–435
  • Mizushima N, Levine B. Autophagy in mammalian development and differentiation. Nat Cell Biol 2010;12:823–30
  • Rubinsztein DC, Codogno P, Levine B. Autophagy modulation as a potential therapeutic target for diverse diseases. Nat Rev Drug Discov 2012;11:709–30
  • White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer 2012;12:401–10
  • Ramakrishnan S, Nguygen TMB, Subramanian IV, Kelekar A. Autophagy and angiogenesis inhibition. Autophagy 2007;3:512–15
  • Nguyen TMB, Subramanian IV, Xiao X, Ghosh G, Nguyen P, Kelekar A, Ramakrishnan S. Endostatin induces autophagy in endothelial cells by modulating Beclin 1 and β-catenin levels. J Cell Mol Med 2009;13:3687–98
  • Lock R, Debnath J. Extracellular matrix regulation of autophagy. Curr Opin Cell Biol 2008;20:583–8
  • Neill T, Schaefer L, Iozzo RV. Instructive roles of extracellular matrix on autophagy. Am J Pathol 2014;184:2146–53
  • Levine B, Kroemer G. Autophagy in the pathogenesis of disease. Cell 2008;132:27–42
  • Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues. Cell 2011;147:728–41
  • Buraschi S, Neill T, Goyal A, Poluzzi C, Smythies J, Owens RT, Schaefer L, Torres AT, Iozzo RV. Decorin causes autophagy in endothelial cells via Peg3. Proc Natl Acad Sci USA 2013;110:E2582–91
  • Thadikkaran L, Crettaz D, Siegenthaler MA, Gallot D, Sapin V, Iozzo RV, Queloz PA, Schneider P, Tissot JD. The role of proteomics in the assessment of premature rupture of fetal membranes. Clin Chim Acta 2005;360:27–36
  • Parker TJ, Sampson DL, Broszczak D, Chng YL, Carter SL, Leavesley DI, Parker AW, Upton Z. A fragment of the LG3 peptide of endorepellin is present in the urine of physically active mining workers: a potential marker of physical activity. PLoS One 2012;7:e33714
  • Surin B, Sachon E, Rougier J-P, Steverlynck C, Garreau C, Lelongt B, Ronco P, Piedagnel R. LG3 fragment of endorepellin is a possible biomarker of severity in lgA nephropathy. Proteomics 2013;13:142–152
  • Soulez M, Pilon E-A, Dieudé M, Cardinal H, Brassard N, Qi S, Wu S-J, Durocher Y, Madore F, Perreault C, Hébert M-J. The perlecan fragment LG3 is a novel regulator of obliterative remodeling associated with allograft vascular rejection. Circ Res 2012;110:94–104
  • Krishna J, Shah ZA, Merchant M, Klein JB, Gozal D. Urinary protein expression patterns in children with sleep-disordered breathing: preliminary findings. Sleep Med 2006;7:221–7
  • Raymond M-A, Désormeaux A, Laplante P, Vigneault N, Filep JG, Landry K, Pshezhetsky AV, Hébert M-J. Apoptosis of endothelial cells triggers a caspase-dependent anti-apoptotic paracrine loop active on vascular smooth muscle cells. FASEB J 2004;18:705–7
  • Laplante P, Raymond MA, Gagnon G, Vigneault N, Sasseville AM, Langelier Y, Bernard M, Raymond Y, Hebért M-J. Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. J Immunol 2005;174:5740–9
  • Mauri P, Scarpa A, Nascimbeni AC, Benazzi L, Parmagnani E, Mafficini A, Della Peruta M, Bassi C, Miyazaki K, Sorio C. Identification of proteins released by pancreatic cancer cells by multidimensional protein identification technology: a strategy for identification of novel cancer markers. FASEB J 2005;19:1125–7
  • Grønborg M, Kristiansen TZ, Iwahori A, Chang R, Reddy R, Sato N, Molina H, Jensen O N, Hruban RH, Goggins MG, Maitra A, Pandey A. Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol Cell Proteom 2006;5:157–71
  • Aspinall-O'Dea M, Costello E. The pancreatic cancer proteome – recent advances and future promise. Proteomics Clin Appl 2007;1:1066–79
  • Chang JW, Kang U-B, Kim DH, Yi JK, Lee JW, Noh D-Y, Lee C, Yu M-H. Identification of circulating endorepellin LG3 fragment: potential use as a serological biomarker for breast cancer. Proteom Clin Appl 2008;2:23–32

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.