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http://dx.doi.org/10.1007/s10059-009-0069-0

Basement Membrane Proteoglycans: Modulators Par Excellence of Cancer Growth and Angiogenesis  

Iozzo, Renato V. (Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University)
Zoeller, Jason J. (Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University)
Nystrom, Alexander (Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University)
Abstract
Proteoglycans located in basement membranes, the nanostructures underling epithelial and endothelial layers, are unique in several respects. They are usually large, elongated molecules with a collage of domains that share structural and functional homology with numerous extracellular matrix proteins, growth factors and surface receptors. They mainly carry heparan sulfate side chains and these contribute not only to storing and preserving the biological activity of various heparan sulfate-binding cytokines and growth factors, but also in presenting them in a more "active configuration" to their cognate receptors. Abnormal expression or deregulated function of these proteoglycans affect cancer and angiogenesis, and are critical for the evolution of the tumor microenvironment. This review will focus on the functional roles of the major heparan sulfate proteoglycans from basement membrane zones: perlecan, agrin and collagen XVIII, and on their roles in modulating cancer growth and angiogenesis.
Keywords
agrin; angiogenesis; cancer; collagen XVIII; endorepellin; endostatin; heparan sulfate proteoglycans; perlecan;
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1 Adkins, J.N., Varnum, S.M., Auberry, K.J., Moore, R.J., Angell, N.H., Smith, R.D., Springer, D.L., and Pounds, J.G. (2002). Toward a human blood serum proteome. Analysis by multidimensional separation coupled with mass spectrometry. Mol. Cell. Proteom.1, 947-955   DOI
2 Batmunkh, E., T$\trai, P., Szab$\"{o}$ , E., L$\"{o}$ di, C., Holczbauer, A., P$\ska, C., Kupcsulik, P., Kiss, A., Schaff, Z., and Kovalszky, I. (2007). Comparison of the expression of agrin, a basement membrane heparan sulfate proteoglycan, in cholangiocarcinoma and hepatocellular carcinoma. Hum. Pathol. 38, 1508-1515   DOI   PUBMED   ScienceOn
3 Bix, G., and Iozzo, R.V. (2005). Matrix revolutions: 'tails' of basement-membrane components with angiostatic functions. Trends Cell Biol. 15, 52-60   DOI   PUBMED   ScienceOn
4 Cohen, I.R., Murdoch, A.D., Naso, M.F., Marchetti, D., Berd, D., and Iozzo, R.V. (1994). Abnormal expression of perlecan proteoglycan in metastatic melanomas. Cancer Res. 54, 5771-5774   PUBMED
5 Costell, M., Carmona, R., Gustafsson, E., Gonzalez-Iriarte, M., Fassler, R., and Munoz-Chapuli, R. (2002). Hyperplastic conotruncal endo-cardial cushions and transposition of great arteries in perlecan-null mice. Circ. Res. 91, 158-164   DOI   PUBMED   ScienceOn
6 Dhanabal, M., Ramchandran, R., Waterman, M.J., Lu, H., Knebelmann, B., Segal, M., and Sukhatme, V.P. (1999). Endostatin induces endothelial cell apoptosis. J. Biol. Chem. 274, 11721-11726   DOI   PUBMED   ScienceOn
7 Donahue, J.E., Berzin, T.M., Rafii, M.S., Glass, D.J., Yancopoulos, G.D., Fallon, J.R., and Stopa, E.G. (1999). Agrin in Alzheimer's disease: Altered solubility and abnormal distribution within microvasculature and brain parenchyma. Proc. Natl. Acad. Sci.USA 96, 6468-6472   DOI   PUBMED   ScienceOn
8 Ferreras, M., Felbor, U., Lenhard, T., Olsen, B.R., and Delaisse, J. (2000). Generation and degradation of human endostatin proteins by various proteinases. FEBS Lett. 486, 247-251   DOI   PUBMED   ScienceOn
9 Gronborg, M., Kristiansen, T.Z., Iwahori, A., Chang, R., Reddy, R., Sato, N., Molina, H., Jensen, O.N., Hruban, R.H., Goggins, M.G., et al. (2006). Biomarker discovery from pancreatic cancer secretome using a differential proteomic approach. Mol. Cell. Proteom. 5, 157-171   DOI   ScienceOn
10 Halfter, W., Dong, S., Schurer, B., and Cole, G.J. (1998). Collagen XVIII is a basement membrane heparan sulfate proteoglycan. J. Biol. Chem. 273, 25404-25412   DOI   PUBMED   ScienceOn
11 Hilgenberg, L.G.W., Su, H., Gu, H., O'Dowd, D.K., and Smith, M.A. (2006). $\alpha$3$Na^{+}$/$K^{+}$-ATPase is a neuronal receptor for agrin. Cell 125, 359-369   DOI   PUBMED   ScienceOn
12 Iozzo, R.V. (1994). Perlecan: a gem of a proteoglycan. Matrix Biol. 14, 203-208   DOI   PUBMED   ScienceOn
13 Krishna, J., Shah, Z.A., Merchant, M., Klein, J.B., and Gozal, D. (2006). Urinary protein expression patterns in children with sleep-disordered breathing: preliminary findings. Sleep Med. 7, 221-227   DOI   PUBMED   ScienceOn
14 Laplante, P., Raymond, M.-A., Labelle, A., Abe, J.-I., Iozzo, R.V., and Hebert, M.-J. (2006). Perlecan proteolysis induces $\alpha$2 $\beta$1 integrin and src-family kinases dependent anti-apoptotic pathway in fibroblasts in the absence of focal adhesion kinase activation. J. Biol. Chem. 281, 30383-30392   DOI   PUBMED   ScienceOn
15 Nitkin, R.M., Smith, M.A., Magill, C., Fallon, J.R., Yao, Y.-M.M., Wallace, B.G., and McMahan, U.J. (1987). Identification of agrin, a synaptic organizing protein from Torpedo electric organ. J. Cell Biol. 105, 2471-2478   DOI   PUBMED
16 Li, Q., and Olsen, B.R. (2004). Increased angiogenic response in aortic explants of collagen XVIII/endostatin-null mice. Am. J. Pathol. 165, 415-424   DOI   PUBMED   ScienceOn
17 Marneros, A.G., and Olsen, B.R. (2005). Physiological role of collagen XVIII and endostatin. FASEB J. 19, 716-728   DOI   PUBMED   ScienceOn
18 Marneros, A.G., She, H., Zambarakji, H., Hashizume, H., Connolly, E.J., Kim, I., Gragoudas, E.S., Miller, J.W., and Olsen, B.R. (2007). Endogenous endostatin inhibits choroidal neovascularization. FASEB J. 21, 3809-3818   DOI   PUBMED   ScienceOn
19 Oh, S.P., Kamagata, Y., Muragaki, Y., Timmons, S., Ooshima, A., and Olsen, B.R. (1994a). Isolation and sequencing of cDNAs for proteins with multiple domains of Gly-Xaa-Yaa repeats identify a distinct family of collagenous proteins. Proc. Natl. Acad. Sci. USA 91, 4229-4233   DOI   PUBMED   ScienceOn
20 Rehn, M., Hintikka, E., and Pihlajaniemi, T. (1994). Primary structure of the a1 chain of mouse type XVIII collagen, partial structure of the corresponding gene, and comparison of the $\alpha$1(XVIII) chain with its homologue, the $\alpha$1 (XV) collagen chain. J. Biol. Chem. 269, 13929-13935   PUBMED
21 Rossi, M., Morita, H., Sormunen, R., Airenne, S., Kreivi, M., Wang, L., Fukai, N., Olsen, B.R., Tryggvason, K., and Soininen, R. (2003). Heparan sulfate chains of perlecan are indispensable in the lens capsule but not in the kidney. EMBO J. 22, 236-245   DOI   PUBMED   ScienceOn
22 T$\trai, P., Dudas, J., Batmunkh, E., M$\th$\, M., Zalatnai, A., Schaff, Z., Ramadori, G., and Kovalszky, I. (2006). Agrin, a novel basement membrane component in human rat and liver, accumulates in cirrhosis and hepatocellular carcinoma. Lab. Invest. 86, 1149-1160   PUBMED
23 Sauter, B.V., Martinet, O., Zhang, W.-J., Mandeli, J., and Woo, S.L.C. (2001). Adenovirus-mediated gene transfer of endostatin vivo results in high level of transgene expression and inhibition of tumor growth and metastasis. Proc. Natl. Acad. Sci. USA 97, 4802-4807   DOI   ScienceOn
24 Scotton, P., Bleckmann, D., Stebler, M., Sciandra, F., Brancaccio, A., Meier, T., Stetefeld, J., and Ruegg, M.A. (2006). Activation of muscle-specific receptor tyrosine kinase and binding to dystroglycan are regulated by alternative mRNA splicing of agrin. J. Biol. Chem. 281, 36835-36845   DOI   PUBMED   ScienceOn
25 Seppinen, L., Sormunen, R., Soini, Y., Elamaa, H., Heljasvaara, R., and Pihlajaniemi, T. (2008). Lack of collagen XVIII accelerates cutaneous wound healing, while overexpression of its endostatin domain leads to delayed healing. Matrix Biol. 102, 535-546   DOI   PUBMED   ScienceOn
26 Tran, P.-K., Tran-Lundmark, K., Soininen, R., Tryggvason, K., Thyberg, J., and Hedin, U. (2004). Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan. Circ. Res. 94, 550-558   DOI   PUBMED   ScienceOn
27 Wickstr$\"{o}$m, S.A., Alitalo, K., and Keski-Oja, J. (2005). Endostatin signaling and regulation of endothelial cell-matrix interactions. Adv. Cancer Res. 94, 197-229   DOI   ScienceOn
28 Woodall, B.P., Nystr$\"{o}$m, A., Iozzo, R.A., Eble, J.A., Niland, S., Krieg, T., Eckes, B., Pozzi, A., and Iozzo, R.V. (2008). Integrin $\alpha$2$\beta$1 is the required receptor for endorepellin angiostatic activity. J. Biol.Chem. 283, 2335-2343   DOI   PUBMED   ScienceOn
29 Winzen, U., Cole, G.J., and Halfter, W. (2003). Agrin is a chimeric proteoglycan with the attachment sites for heparan sulfate/chondroitin sulfate located in two multiple serine-glycine clusters. J. Biol. Chem. 278, 30106-30114   DOI   PUBMED   ScienceOn
30 Witmer, A.N., van den Born, J., Vrensen, G.F.J.M., and Schlingemann, R.O. (2001). Vascular localization of heparan sulfate proteoglycans in retinas of patients with diabetes mellitus and in VEGF-induced retinopathy using domain-specific antibodies.Curr. Eye Res. 22, 190-197   DOI   PUBMED   ScienceOn
31 Zhang, Z., Ramirez, N.E., Yankeelov, T.E., Li, Z., Ford, L.E., Qi, Y., Pozzi, A., and Zutter, M.M. (2008). $\alpha$2$\beta$1 integrin expression in the tumor microenvironment enhances tumor angiogenesis in a tumor cell-specific manner. Blood 111, 1980-1988   DOI   PUBMED   ScienceOn
32 Zorick, T.S., Mustacchi, Z., Bando, S.Y., Zatz, M., Moreira-Filho, C.A., Olsen, B., and Passos-Bueno, M.R. (2001). High serum endostatin levels in Down syndrome: Implications for improved treatment and prevention of solid tumors. Eur. J. Hum. Genet. 9, 811-814   DOI   ScienceOn
33 Zhang, J., Wang, Y., Chu, Y., Su, L., Gong, Y., Zhang, R., and Xiong, S. (2006). Agrin is involved in lymphocytes activation that is mediated by $\alpha$-dystroglycan. FASEB J. 20, 50-58   DOI   PUBMED   ScienceOn
34 Yurchenco, P.D., Amenta, P.S., and Patton, B.L. (2004). Basement membrane assembly, stability and activities observed through a developmental lens. Matrix Biol. 22, 521-538   DOI   PUBMED   ScienceOn
35 Aviezer, D., Iozzo, R.V., Noonan, D.M., and Yayon, A. (1997). Suppression of autocrine and paracrine functions of basic fibroblast growth factor by stable expression of perlecan antisense cDNA. Mol. Cell. Biol. 17, 1938-1946   DOI   PUBMED
36 Kim, Y.-M., Hwang, S., Kim, Y.-M., Pyun, B.-J., Kim, T.-Y., Lee, S.-T., Gho, Y.S., and Kwon, Y.-G. (2002). Endostatin blocks vascular endothelial growth factor-mediated signaling via direct interaction with KDR/Flk-1. J. Biol. Chem. 277, 27872-27879   DOI   PUBMED   ScienceOn
37 Reiland, J., Sanderson, R.D., Waguespack, M., Barker, S.A., Long, R., Carson, D.D., and Marchetti, D. (2004). Heparanase degrades syndecan-1 and perlecan heparan sulfate: functional implications for tumor cell invasion. J. Biol. Chem. 279, 8047-8055   DOI   PUBMED   ScienceOn
38 Klein, G., Conzelmann, S., Beck, S., Timpl, R., and Muller, C.A. (1995). Perlecan in human bone marrow: a growth-factor presenting, but anti-adhesive, extracellular matrix component for hematopoietic cells. Matrix Biol. 14, 457-465   DOI   PUBMED   ScienceOn
39 O'Reilly, M.S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W.S., Flynn, E., Birkhead, J.R., Olsen, B.R., and Folkman, J. (1997). Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 88, 277-285   DOI   PUBMED   ScienceOn
40 Senger, D.R., Perruzzi, C.A., Streit, M., Koteliansky, V.E., de Fougerolles, A.R., and Detmar, M. (2002). The $\alpha$1$\beta$1 and $\alpha$2$\beta$1 integrins provide critical support for vascular endothelial growth factor signaling, endothelial cell migration, and tumor angiogenesis. Am. J. Pathol. 160, 195-204   DOI   PUBMED   ScienceOn
41 Zweers, M.C., Davidson, J.M., Pozzi, A., Hallinger, R., Janz, K., Quondamatteo, F., Leutgeb, B., Krieg, T., and Eckes, B. (2007). Integrin $\alpha$2$\beta$1 is required for regulation of murine wound angiogenesis but is dispensable for reepithelialization. J. Invest. Dermatol. 127, 467-478   DOI   ScienceOn
42 Dong, S., Cole, G.J., and Halfter, W. (2003). Expression of collagen XVIII and localization of its glycosaminoglycan attachment sites. J. Biol. Chem. 278, 1700-1707   DOI   PUBMED   ScienceOn
43 Clamp, A.R., and Jayson, G.C. (2005). The clinical potential of antiangiogenic fragments of extracellular matrix proteins. Br. J.Cancer 93, 967-972   DOI   PUBMED   ScienceOn
44 Gautam, M., Noakes, P.G., Moscoso, L., Rupp, F., Scheller, R.H., Merlie, J.P., and Sanes, J.R. (1996). Defective neuromuscular synaptogenesis in agrin-deficient mice. Cell 85, 525-535   DOI   PUBMED   ScienceOn
45 Grenache, D.G., Zhang, Z., Wells, L.E., Santoro, S.A., Davidson, J.M., and Zutter, M.M. (2006). Wound healing in the $\alpha$2 $\beta$1 integrin-deficient mouse: altered keratinocyte biology and dysregulated matrix metalloproteinase expression. J. Invest. Dermatol. 127, 455-466   DOI   PUBMED   ScienceOn
46 Cailhier, J.-F., Sirois, I., Raymond, M.-A., Lepage, S., Laplante, P., Brassard, N., Prat, A., Iozzo, R.V., Pshezhetsky, A.V., and Hebert, M.-J. (2008). Caspase-3 activation triggers extracellular release of cathepsin L and endorepellin proteolysis. J. Biol. Chem. 283, 27220-27229   DOI   PUBMED   ScienceOn
47 Gonz$\lez-Iriarte, M., Carmona, R., Perez-Pomares, J.M., Macías, D., Costell, M., and Munoz-Chapuli, R. (2003). Development of the coronary arteries in a murine model of transposition of great arteries. J. Mol. Cell. Cardio. 35, 795-802   DOI   ScienceOn
48 Zhou, Z., Wang, J., Cao, R., Morita, H., Soininen, R., Chan, K.M., Liu, B., Cao, Y., and Tryggvason, K. (2004). Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice. Cancer Res. 64, 4699-4702   DOI   ScienceOn
49 Lin, S., Maj, M., Bezakova, G., Magyar, J.P., Brenner, H.R., and Ruegg, M.A. (2008). Muscle-wide secretion of a miniaturized form of neural agrin rescues focal neuromuscular innervation in agrin mutant mice. Proc. Natl. Acad. Sci. USA 105, 11406-11411   DOI   PUBMED   ScienceOn
50 Sudhakar, A., Sugimoto, H., Yang, C., Lively, J., Zeisberg, M., and Kalluri, R. (2003). Human tumstatin and human endostatin exhibit distinct antiangiogenic activities mediated by $\alpha$v$\beta$3 and $\alpha$5$\beta$1 integrins. Proc. Natl. Acad. Sci. USA 100, 4766-4771   DOI   PUBMED   ScienceOn
51 Iozzo, R.V., and San Antonio, J.D. (2001). Heparan sulfate proteoglycans: heavy hitters in the angiogenesis arena. J. Clin. Invest. 108, 349-355   DOI   ScienceOn
52 Kadenhe-Chiweshe, A., Papa, J., McCrudden, K.W., Frischer, J., Bae, J.-O., Huang, J., Fisher, J., Lefkowitch, J.H., Feirt, N., Rudge, J., et al. (2008). Sustained VEGF blockade results in mi croenvironmental sequestration of VEGF by tumors and persistent VEGF receptor-2 activation. Mol. Cancer Res. 6, 1-9   DOI   PUBMED   ScienceOn
53 Verbeek, M.M., Otte-H$\"{o}$ller, I., van den Born, J., van den Heuvel, L.P.W.J., David, G., Wesseling, P., and de Waal, R.M. (1999). Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimer's disease brain. Am. J. Pathol. 155, 2115-2125   DOI   PUBMED   ScienceOn
54 Denzer, A.J., Sculthess, T., Fauser, C., Schumacher, B., Kammerer, R.A., Engel, J., and Ruegg, M.A. (1998). Electron microscopic structure of agrin and mapping of its binding site in laminin-1. EMBO J. 17, 335-343   DOI   PUBMED   ScienceOn
55 Fuki, I., Iozzo, R.V., and Williams, K.J. (2000). Perlecan heparan sulfate proteoglycan. A novel receptor that mediates a distinct pathway for ligand catabolism. J. Biol. Chem. 275, 25742-25750   DOI   PUBMED   ScienceOn
56 Iozzo, R.V. (2005). Basement membrane proteoglycans: from cellar to ceiling. Nature Rev. Mol. Cell Biol. 6, 646-656   DOI   ScienceOn
57 Iozzo, R.V., Pillarisetti, J., Sharma, B., Murdoch, A.D., Danielson, K.G., Uitto, J., and Mauviel, A. (1997). Structural and functional characterization of the human perlecan gene promoter. Transcriptional activation by transforming growth factor-$\beta$ via a nuclear factor 1-binding element. J. Biol. Chem. 272, 5219-5228   DOI   PUBMED   ScienceOn
58 Tsangaris, G.T., Karamessinis, P., Kolialexi, A., Garbis, S.D., Antsaklis, A., Mavrou, A., and Fountoulakis, M. (2006). Proteomic analysis of amniotic fluid in pregnancies with Down syndrome. Proteomics 6, 4410-4419   DOI   PUBMED   ScienceOn
59 Arikawa-Hirasawa, E., Watanabe, E., Takami, H., Hassell, J.R., and Yamada, Y. (1999). Perlecan is essential for cartilage and cephalic development. Nature Genet. 23, 354-358   DOI   PUBMED   ScienceOn
60 Hassell, J.R., Yamada, Y., and Arikawa-Hirasawa, E. (2003). Role of perlecan in skeletal development and diseases. Glycoconj. J. 19, 263-267   DOI   ScienceOn
61 Nyberg, P., Xie, L., and Kalluri, R. (2005). Endogenous inhibitors of angiogenesis. Cancer Res. 65, 3967-3979   DOI   PUBMED   ScienceOn
62 Vuadens, F., Benay, C., Crettaz, D., Gallot, D., Sapin, V., Schneider, P., Binevenut, W.-V., L$\mery, D., Quadroni, M., Dastugue, B., et al. (2003). Identification of biologic markers of the premature rupture of fetal membranes: proteomic approach. Proteomics 3, 1521-1525   DOI   PUBMED   ScienceOn
63 Kuo, C.J., LaMontagne, K.R., Garcia-Cardena, G., Ackley, B.D., Kalman, D., Park, S., Christofferson, R., Kamihara, J., Ding,Y.-H., Lo, K.-M., et al. (2001). Oligomerization-dependent regulation of motility and morphogenesis by the collagen XVIII NC1/ endostatin domain. J. Cell Biol. 152, 1233-1246   DOI   PUBMED
64 Mongiat, M., Sweeney, S., San Antonio, J.D., Fu, J., and Iozzo, R.V. (2003). Endorepellin, a novel inhibitor of angiogenesis derived from the C terminus of perlecan. J. Biol. Chem. 278, 4238-4249   DOI   PUBMED   ScienceOn
65 Moulton, K.S., Olsen, B.R., Sonn, S., Fukai, N., Zurakowski, D., and Zeng, X. (2004). Loss of collagen XVIII enhances neovascularization and vascular permeability in atherosclerosis. Circulation 110, 1330-1336   DOI   PUBMED   ScienceOn
66 Warth, A., Kr$\"{o}$ger, S., and Wolburg, H. (2004). Redistribution of aquaporin-4 in human glioblastoma correlates with loss of agrin immunoreactivity from brain capillary basal laminae. Acta Neuropathol. 107, 311-318   DOI   PUBMED
67 Whitelock, J.M., Graham, L.D., Melrose, J., Murdoch, A.D., Iozzo, R.V., and Underwood, P.A. (1999). Human perlecan immunopurified from different endothelial cell sources has different adhesive properties for vascular cells. Matrix Biol. 18, 163-178   DOI   PUBMED   ScienceOn
68 Burgess, R.W., Dickman, D.K., Nunez, L., Glass, D.J., and Sanes, J.R. (2002). Mapping sites responsible for interactions of agrin with neurons. J. Neurochem. 83, 271-284   DOI   PUBMED   ScienceOn
69 Gesemann, M., Brancaccio, A., Schumacher, B., and Ruegg, M.A. (1998). Agrin is a high-affinity binding protein of dystroglycan in non-muscle tissue. J. Biol. Chem. 273, 600-605   DOI   PUBMED   ScienceOn
70 Lin, W., Burgess, R.W., Dominguez, B., Pfaff, S.L., Sanes, J.R., and Lee, K.-F. (2001). Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410, 1057-1064   DOI   PUBMED   ScienceOn
71 Elamaa, H., Snellman, A., Rehn, M., Autio-Harmainen, H., and Pihlajaniemi, T. (2003). Characterization of the human type XVIII collagen gene and proteolytic processing and tissue location of the variant containing a frizzled motif. Matrix Biol. 22, 427-442   DOI   PUBMED   ScienceOn
72 Sasaki, T., Fukai, N., Mann, K., Gohring, W., Olsen, B.R., and Timpl, R. (1998). Structure, function and tissue forms of the C-terminal globular domain of collagen XVIII containing the angiogenesis inhibitor endostatin. EMBO J. 17, 4249-4256   DOI   PUBMED   ScienceOn
73 Whitelock, J.M., Melrose, J., and Iozzo, R.V. (2008). Diverse cell signaling events modulated by perlecan. Biochemistry 47, 11174-11183   DOI   PUBMED   ScienceOn
74 Matsumoto-Miyai, K., Sokolowska, E., Zurlinden, A., Gee, C.E., Luscher, D., Hettwer, S., Wolfel, J., Ladner, A.P., Ster, J., Gerber, U., et al. (2009). Coincident pre- and postsynaptic activation induces dendritic filopodia via neurotrypsin-dependent agrin cleavage. Cell 136, 1161-1171   DOI   PUBMED   ScienceOn
75 Menzel, O., Bekkeheien, R.C., Reymond, A., Fukai, N., Boye, E., Kosztolanyi, G., Aftimos, S., Deutsch, S., Scott, H.S., Olsen, B.R., et al. (2004). Knobloch syndrome: novel mutations in COL18A1, evidence for genetic heterogeneity, and a functionally impaired polymorphism in endostatin. Hum. Mutat. 23, 77-84   DOI   PUBMED   ScienceOn
76 Aviezer, D., Hecht, D., Safran, M., Eisinger, M., David, G., and Yayon, A. (1994). Perlecan, basal lamina proteoglycan, promotes basic fibroblast growth factor-receptor binding, mitogenesis,and angiogenesis. Cell 79, 1005-1013   DOI   PUBMED   ScienceOn
77 Bix, G., Castello, R., Burrows, M., Zoeller, J.J., Weech, M., Iozzo, R.A., Cardi, C., Thakur, M.T., Barker, C.A., Camphausen, K.C., et al. (2006). Endorepellin in vivo: targeting the tumor vasculature and retarding cancer growth and metabolism. J. Natl. Cancer Inst. 98, 1634-1646   DOI   PUBMED   ScienceOn
78 Marneros, A.G., Keene, D.R., Hansen, U., Fukai, N., Moulton, K., Goletz, P.L., Moiseyev, G., Pawlyk, B.S., Halfter, W., Dong, S., et al. (2004). Collagen XVIII/endostatin is essential for vision and retinal pigment epithelial function. EMBO J. 23, 89-99   DOI   PUBMED   ScienceOn
79 Robinson, C.J., Mulloy, B., Gallagher, J.T., and Stringer, S.E. (2006). VEGF165-binding sites within heparan sulfate encompass two highly sulfated domains and can be liberated by K5 lyase. J. Biol. Chem. 281, 1731-1740   DOI   PUBMED   ScienceOn
80 Utriainen, A., Sormunen, R., Kettunen, M., Carvalhaes, L.S., Sajanti, E., Eklund, L., Kauppinen, R., Kitten, G.T., and Pihlajaniemi, T. (2004). Structurally altered basement membranes and hydrocephalus in a type XVIII collagen deficient mouse line. Human Mol. Gen. 13, 2089-2099   DOI   ScienceOn
81 Farach-Carson, M.C., and Carson, D.D. (2007). Perlecan - a multifunctional extracellular proteoglycan scaffold. Glycobiology 17, 897-905   DOI   PUBMED   ScienceOn
82 Ghiselli, G., Eichstetter, I., and Iozzo, R.V. (2001). A role for the perlecan protein core in the activation of the keratinocyte growth factor receptor. Biochem. J. 359, 153-163   DOI   PUBMED   ScienceOn
83 Nugent, M.A., and Iozzo, R.V. (2000). Fibroblast growth factor-2. Int. J. Biochem. Cell Biol. 32, 115-120   DOI   PUBMED   ScienceOn
84 Oh, S.P., Warman, M.L., Seldin, M.F., Cheng, S.-D., Knoll, J.H.M., Timmons, S., and Olsen, B.R. (1994b). Cloning of cDNA and genomic DNA encoding human type XVIII collagen and localization of the $\alpha$1(XVIII) collagen gene to mouse chromosome 10 and human chromosome 21. Genomics 19, 494-499   DOI   PUBMED   ScienceOn
85 Fukai, N., Eklund, L., Marneros, A.G., Oh, S.P., Keene, D.R., Tamarkin, L., Niemela, M., Ilves, M., Li, E., Pihlajaniemi, T., et al. (2002). Lack of collagen XVIII/endostatin results in eye abnormalities. EMBO J. 21, 1535-1544   DOI   PUBMED   ScienceOn
86 Iozzo, R.V., Cohen, I.R., Grassel, S., and Murdoch, A.D. (1994). The biology of perlecan: the multifaceted heparan sulphate proteoglycan of basement membranes and pericellular matrices. Biochem. J. 302, 625-639   DOI   PUBMED
87 Mathiak, M., Yenisey, C., Grant, D.S., Sharma, B., and Iozzo, R.V. (1997). A role for perlecan in the suppression of growth and invasion in fibrosarcoma cells. Cancer Res. 57, 2130-2136   PUBMED
88 Reif, R., Sales, S., Hettwer, S., Dreier, B., Gisler, C., Wolfel, J., Luscher, D., Zurlinden, A., Stephan, A., Ahmed, S., et al. (2007). Specific cleavage of agrin by neurotrypsin, a synaptic protease linked to mental retardation. FASEB J. 21, 3468-3478   DOI   PUBMED   ScienceOn
89 Costell, M., Gustafsson, E., Aszodi, A., Morgelin, M., Bloch, W., Hunziker, E., Addicks, K., Timpl, R., and Fassler, R. (1999). Perlecan maintains the integrity of cartilage and some basement membranes. J. Cell Biol. 147, 1109-1122   DOI   PUBMED
90 Bix, G., and Iozzo, R.V. (2008). Novel interactions of perlecan: Unraveling perlecan's role in angiogenesis. Microsc. Res. 71, 339-348   DOI   ScienceOn
91 Karumanchi, S.A., Jha, V., Ramchandran, R., Karihaloo, A., Tsiokas, L., Chan, B., Dhanabai, M., Hanai, J.-C., Venkataraman, G., Shriver, Z., et al. (2001). Cell surface glypicans are low-affinity endostatin receptors. Mol. Cell 7, 811-822   DOI   PUBMED   ScienceOn
92 Sharma, B., Handler, M., Eichstetter, I., Whitelock, J., Nugent, M.A., and Iozzo, R.V. (1998). Antisense targeting of perlecan blocks tumor growth and angiogenesis in vivo. J. Clin. Invest. 102, 1599-1608   DOI   PUBMED   ScienceOn
93 Savor$\, C., Zhang, C., Muir, C., Liu, R., Wyrwa, J., Shu, J., Zhau, H.E., Chung, L.W., Carson, D.D., and Farach-Carson, M.C. (2005). Perlecan knockdown in metastatic prostate cancer cells reduces heparin-binding growth factor responses in vitro and tumor growth in vivo. Clin. Exp. Metastasis 22, 377-390   DOI
94 Zatterstrom, U.K., Felbor, U., Fukai, N., and Olsen, B.R. (2000). Collagen XVIII/endostatin structure and functional role in angiogenesis. Cell Struct. Funct. 25, 97-101   DOI   PUBMED   ScienceOn
95 Iozzo, R.V., and Murdoch, A.D. (1996). Proteoglycans of the extracellular environment: clues from the gene and protein side offer novel perspectives in molecular diversity and function. FASEB J. 10, 598-614   DOI   PUBMED
96 Sund, M., Zeisberg, M., and Kalluri, R. (2005). Endogenous stimulators and inhibitors of angiogenesis in gastrointestinal cancers: basic science to clinical application. Gastroenterology 129, 2076-2091   DOI   PUBMED   ScienceOn
97 Gonzalez, E.M., Reed, C.C., Bix, G., Fu, J., Zhang, Y., Gopalakrishnan, B., Greenspan, D.S., and Iozzo, R.V. (2005). BMP-1/Tolloid-like metalloproteases process endorepellin, the angiostatic C-terminal fragment of perlecan. J. Biol. Chem. 280, 7080-7087   DOI   PUBMED   ScienceOn
98 Nugent, M.A., Nugent, H.M., Iozzo, R.V., Sanchack, K., and Edelman, E.R. (2000). 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 97, 6722-6727   DOI   PUBMED   ScienceOn
99 Suzuki, O.T., Sertie, A.L., Der, K.V., Kok, F., Carpenter, M., Murray, J., Czeizel, A.E., Kliemann, S.E., Rosemberg, S., Monteiro, M., et al. (2002). Molecular analysis of collagen XVIII reveals novel mutations, presence of a third isoform, and possible genetic heterogeneity in Knobloch syndrome. Am. J. Hum. Genet. 71, 1320-1329   DOI   PUBMED   ScienceOn
100 Ylik$\"{a}$rpp$\"{a}$, R., Eklund, L., Sormunen, R., Kontiola, A.I., Utriainen, A., M$\"{a}$$\"{a}$tt$\"{a}$, M., Fukai, N., and Olsen, B.R. (2003). Lack of type XVIII collagen results in anterior ocular defects. FASEB J. 17, 2257-2259   DOI   PUBMED
101 Mongiat, M., Otto, J., Oldershaw, R., Ferrer, F., Sato, J.D., and Iozzo, R.V. (2001). Fibroblast growth factor-binding protein is a novel partner for perlecan protein core. J. Biol. Chem. 276, 10263-10271   DOI   PUBMED   ScienceOn
102 Kim, N., Stiegler, A.L., Cameron, T.O., Hallock, P.T., Gomez, A.M.,Huang, J.H., Hubbard, S.R., Dustin, M.L., and Burden, S.J. (2008). Lrp4 is a receptor for agrin and forms a complex with MuSK. Cell 135, 334-342   DOI   ScienceOn
103 Abdollahi, A., Hahnfeldt, P., Maercker, C., Gr$\"{o}$ne, H.-J., Debus, J., Ansorge, W., Folkman, J., Hlatky, L., and Huber, P.E. (2004). Endostatin's antioangiogenic signaling network. Mol. Cell 13, 649-663   DOI   ScienceOn
104 Bezakova, G., and Ruegg, M.A. (2003). New insights into the roles of agrin. Nature Rev. Mol. Cell Biol. 4, 295-308   DOI   ScienceOn
105 Sweeney, S.M., DiLullo, G., Slater, S.J., Martinez, J., Iozzo, R.V., Lauer-Fields, J.L., Fields, G.B., and San Antonio, J.D. (2003). Angiogenesis in collagen I requires $\alpha$2$\beta$1 ligation of a GFP$^{*}$GER sequence and possible p38 MAPK activation and focal adhesion disassembly. J. Biol. Chem. 278, 30516-30524   DOI   PUBMED   ScienceOn
106 Whitelock, J.M., Murdoch, A.D., Iozzo, R.V., and Underwood, P.A. (1996). 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. 271, 10079-10086   DOI   PUBMED
107 Zoeller, J.J., McQuillan, A., Whitelock, J., Ho, S.-Y., and Iozzo, R.V. (2008). A central function for perlecan in skeletal muscle and cardiovascular development. J. Cell Biol. 181, 381-394   DOI   ScienceOn
108 Hurskainen, M., Eklund, L., Hagg, P.O., Fruttiger, M., Sormunen, R., IIves, M., and Pihlajaniemi, T. (2005). Abnormal maturation of the retinal vasculature in type XVIII collagen/endostatin deficient mice and changes in retinal glial cells due to lack of collagen types XV and XVIII. FASEB J. 19, 1564-1666   DOI   PUBMED
109 Groffen, A.J.A., Buskens, C.A.F., van Kuppevelt, T.H., Veerkamp, J.H., Monnens, L.A.H., and van den Heuvel, L.P.W.J. (1998). Primary structure and high expression of human agrin in basement membranes of adult lung and kidney. Eur. J. Biochem. 254, 123-128   DOI   PUBMED   ScienceOn
110 Handler, M., Yurchenco, P.D., and Iozzo, R.V. (1997). Developmental expression of perlecan during murine embryogenesis. Dev. Dyn. 210, 130-145   DOI   PUBMED   ScienceOn
111 West, L., Govindraj, P., Koob, T.J., and Hassell, J.R. (2006). Changes in perlecan during chondrocyte differentiation in the fetal bovine rib growth plate. J. Orthop. Res. 24, 1317-1326   DOI   PUBMED   ScienceOn
112 Baerwald-De La Torre, K., Winzen, U., Halfter, W., and Bixby, J.L. (2004). Glycosaminoglycan-dependent and -independent inhibition of neurite outgrowth by agrin. J. Neurochem. 90, 50-61   DOI   PUBMED   ScienceOn
113 Rehn, M., Veikkola, T., Kukk-Valdre, E., Nakamura, H., Ilmonen, M., Lombardo, C.R., Pihlajaniemi, T., Alitalo, K., and Vuori, K. (2001). Interaction of endostatin with integrins implicated in angiogenesis. Proc. Natl. Acad. Sci. USA 98, 1024-1029   DOI   PUBMED   ScienceOn
114 Thadikkaran, L., Crettaz, D., Siegenthaler, M.A., Gallot, D., Sapin, V., Iozzo, R.V., Queloz, P.A., Schneider, P., and Tissot, J.D. (2005). The role of proteomics in the assessment of premature rupture of fetal membranes. Clin. Chim. Acta 360, 27-36   DOI   PUBMED   ScienceOn
115 Whitelock, J.M., and Iozzo, R.V. (2005). Heparan sulfate: a complex polymer charged with biological activity. Chem. Rev. 105, 2745-2764   DOI   PUBMED   ScienceOn
116 Gianazza, E., Wait, R., Begum,S., Eberini, I., Campagnoli, M., Labo, S., and Galliano, M. (2007). Mapping the 5-50-kDa fraction of human amniotic fluid proteins by 2-DE and ESI-MS. Proteomics Clin. Appl. 1, 167-175   DOI   ScienceOn
117 Iozzo, R.V. (1998). Matrix proteoglycans: from molecular design to cellular function. Annu. Rev. Biochem. 67, 609-652   DOI   PUBMED   ScienceOn
118 O'Riordan, E., Orlova, T.N., Mendelev, N., Patschan, D., Kemp, R., Chander, P.N., Hu, R., Hao, G., Gross, S.S., Iozzo, R.V., et al. (2008). Urinary proteomic analysis of chronic renal allograft nephropathy. Proteomics Clin. Appl. 2, 1025-1035   DOI   ScienceOn
119 Saarela, J., Ylikarppa, R., Rehn, M., Purmonen, S., and Pihlajaniemi, T. (1998). Complete primary structure of two variant forms of human type XVIII collagen and tissue-specific differences in the expression of the corresponding transcripts. Matrix Biol. 16, 319-328   DOI   PUBMED   ScienceOn
120 Shichiri, M., and Hirata, Y. (2001). Antiangiogenesis signals by endostatin. FASEB J. 15, 1044-1053   DOI   PUBMED   ScienceOn
121 Raymond, M.-A., Desormeaux, A., Laplante, P., Vigneault, N., Filep, J.G., Landry, K., Pshezhetsky, A.V., and Hebert, M.-J. (2004). Apoptosis of endothelial cells triggers a caspase-dependent anti-apoptotic paracrine loop active on vascular smooth muscle cells. FASEB J. 18, 705-707   DOI   PUBMED   ScienceOn
122 Adatia, R., Albini, A., Carlone, S., Giunciuglio, D., Benelli, R., Santi,L., and Noonan, D.M. (1998). Suppression of invasive behavior of melanoma cells by stable expression of anti-sense perlecan cDNA. Ann. Oncol. 8, 1257-1261
123 Bix, G., Fu, J., Gonzalez, E., Macro, L., Barker, A., Campbell, S., Zutter, M.M., Santoro, S.A., Kim, J.K., H$\"{o}$$\"{o}$k, M., et al. (2004). Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through the $\alpha$2$\beta$1 integrin. J. Cell Biol. 166, 97-109   DOI   PUBMED   ScienceOn
124 Laplante, P., Raymond, M.A., Gagnon, G., Vigneault, N., Sasseville, A.M., Langelier, Y., Bernard, M., Raymond, Y., and Heb$\rt, M.-J. (2005). Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis. J. Immunol. 174, 5740-5749   DOI   PUBMED
125 Bix, G., Iozzo, R.A., Woodall, B., Burrows, M., McQuillan, A., Campbell, S., Fields, G.B., and Iozzo, R.V. (2007). Endorepellin, the C-terminal angiostatic module of perlecan, enhances collagen-platelet responses via the $\alpha$2$\beta$1 integrin receptor. Blood 109,3745-3748   DOI   PUBMED   ScienceOn
126 Chang, J.W., Kang, U.-B., Kim, D.H., Yi, J.K., Lee, J.W., Noh, D.-Y., Lee, C., and Yu, M.-H. (2008). Identification of circulating endorepellin LG3 fragment: Potential use as a serological biomarker for breast cancer. Proteomics Clin. Appl. 2, 23-32   DOI   ScienceOn
127 Mongiat, M., Taylor, K., Otto, J., Aho, S., Uitto, J., Whitelock, J., and Iozzo, R.V. (2000). The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7. J. Biol. Chem. 275, 7095-7100   DOI   PUBMED   ScienceOn
128 Oda, O., Shinzato, T., Ohbayashi, K., Takai, I., Kunimatsu, M., Maeda, K., and Yamanaka, N. (1996). Purification and characterization of perlecan fragment in urine of end-stage renal failure patients. Clin. Chim. Acta 255, 119-132   DOI   PUBMED   ScienceOn
129 Zoeller, J.J., and Iozzo, R.V. (2008). Proteomic profiling of endorepellin angiostatic activity on human endothelial cells. Proteome Sci. 6, 7   DOI   ScienceOn