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Gene Review

HSPG2  -  heparan sulfate proteoglycan 2

Homo sapiens

Synonyms: Basement membrane-specific heparan sulfate proteoglycan core protein, HSPG, PLC, PRCAN, Perlecan, ...
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Disease relevance of HSPG2

  • Mutations in the perlecan gene (HSPG2) cause two classes of skeletal disorders: the relatively mild Schwartz-Jampel syndrome (SJS) and severe neonatal lethal dyssegmental dysplasia, Silverman-Handmaker type (DDSH) [1].
  • In a second independent cohort of 310 Dutch Caucasian intracranial aneurysm patients and 336 Dutch Caucasian controls, the association for the HSPG2 gene [combined odds ratio (OR) 1.33, 95% confidence interval (CI) 1.13-1.57, P=6x10(-4)] was replicated [2].
  • The cell surface heparan sulfate proteoglycan (HSPG) glypican-1 is up-regulated by pancreatic and breast cancer cells, and its removal renders such cells insensitive to many growth factors [3].
  • These data reveal changes in the expression of syndecan-1, syndecan-3, and perlecan in human chronic cholestatic liver disease, that may be important in the deposition of matrix components and activation of growth factors that support ductular reaction and accompanying fibrogenesis [4].
  • In comparison with bile ductular cells of normal liver, reactive ductules in chronic cholestasis were marked by an elevated expression of syndecan-1, surrounded by an increased perlecan expression [4].

Psychiatry related information on HSPG2

  • A genetic association of an intronic single nucleotide polymorphism site of heparan sulfate proteoglycan 2 (HSPG2) with Alzheimer's disease (AD) was investigated among Finnish AD patients (n=213) and controls (n=269) [5].
  • Our results provide preliminary evidence that a PLC isozyme may confer susceptibility to bipolar disorder, probably accounting for a fraction of the total genetic variance [6].
  • Here we determined psychometric functions for perceptual resolution in static displays and dynamic rotating displays (with and without a static preview) as determined by stereopsis and PLC in isolation and with both cues jointly, possibly in conflict [7].
  • An anti-heparan sulfate proteoglycan (HSPG) monoclonal antibody (3G10) recognized irregular round structures (IRSs) of various sizes adjacent to tau-positive intracellular Pick bodies (PBs) in the granular cell layer of the dentate gyrus and the superficial layers of the parahippocampal and other temporal gyri in Pick's disease [8].
  • At its core, the debate is over how and to what extent laws should be formulated to persuade, leverage or coerce (PLC) persons with severe mental illness living in the community to comply with medications that mental health professionals believe they need [9].

High impact information on HSPG2

  • Here we report a homozygous, 89-bp duplication in exon 34 of HSPG2 in a pair of siblings with DDSH born to consanguineous parents, and heterozygous point mutations in the 5' donor site of intron 52 and in the middle of exon 73 in a third, unrelated patient, causing skipping of the entire exons 52 and 73 of the HSPG2 transcript, respectively [10].
  • Biochemically, truncated perlecan was not secreted by the patient fibroblasts, but was degraded to smaller fragments within the cells [10].
  • Perlecan is a large heparan sulfate (HS) proteoglycan present in all basement membranes and in some other tissues such as cartilage, and is implicated in cell growth and differentiation [10].
  • The cartilage matrix from these patients stained poorly with antibody specific for perlecan, but there was staining of intracellular inclusion bodies [10].
  • Perlecan is present in a variety of basement membranes and in other extracellular matrix structures [11].

Chemical compound and disease context of HSPG2


Biological context of HSPG2

  • The complete intron-exon organization of the gene encoding human perlecan (HSPG2), the major heparan sulfate proteoglycan of basement membranes, has been elucidated, and specific exons have been assigned to coding sequences for the modular domains of the protein core [17].
  • The results indicate that the MUC1 SEA domain originated from heparin sulfate proteoglycan of basement membrane (HSPG2; perlecan), an inducer of tumor cell growth [18].
  • 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 [19].
  • The localization of this proteoglycan locus in the human genome and the availability of new RFLPs provide the tools for future studies of human diseases where the HSPG2 proteoglycan gene is suspected to be involved [19].
  • Moreover, the HSPG2 is located on chromosome 1p36, a region of linkage to late-onset AD (LOAD) [12].

Anatomical context of HSPG2


Associations of HSPG2 with chemical compounds

  • We showed also that perlecan bound bFGF specifically by the heparan sulfate chains located on the amino-terminal domain I. Once bound, the growth factor was released very efficiently by stromelysin, rat collagenase, plasmin, heparitinase I, platelet extract, and heparin [23].
  • A codistribution between clusters of acetylcholine receptors and HSPG and laminin and Vicia villosa B4 lectin-positive material exists only in Ultroser G/brain extract-based myotubes like in muscle in vivo [24].
  • The rise in Ca(i)(2+) appears to result from a mobilization of intracellular stores, because the transient was nearly abolished by inhibition of PLC with the phosphatidylinositol-specific PLC inhibitor U-73122, and it was not affected significantly by removal of extracellular Ca(2+) [25].
  • We provide evidence for a novel biological axis that links a soluble fragment of perlecan protein core to the major cell surface receptor for collagen I, alpha2beta1 integrin, and provide an initial investigation of the intracellular signaling events that lead to endorepellin antiangiogenic activity [26].
  • The HSPG could be metabolically labeled with ethanolamine or palmitate, which was partially removed by treatment with PI-PLC [27].

Physical interactions of HSPG2


Enzymatic interactions of HSPG2


Regulatory relationships of HSPG2


Other interactions of HSPG2


Analytical, diagnostic and therapeutic context of HSPG2


  1. Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. Arikawa-Hirasawa, E., Le, A.H., Nishino, I., Nonaka, I., Ho, N.C., Francomano, C.A., Govindraj, P., Hassell, J.R., Devaney, J.M., Spranger, J., Stevenson, R.E., Iannaccone, S., Dalakas, M.C., Yamada, Y. Am. J. Hum. Genet. (2002) [Pubmed]
  2. Evidence in favor of the contribution of genes involved in the maintenance of the extracellular matrix of the arterial wall to the development of intracranial aneurysms. Ruigrok, Y.M., Rinkel, G.J., Van't Slot, R., Wolfs, M., Tang, S., Wijmenga, C. Hum. Mol. Genet. (2006) [Pubmed]
  3. Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells. Ding, K., Lopez-Burks, M., Sánchez-Duran, J.A., Korc, M., Lander, A.D. J. Cell Biol. (2005) [Pubmed]
  4. Heparan sulfate proteoglycan expression in chronic cholestatic human liver diseases. Roskams, T., Rosenbaum, J., De Vos, R., David, G., Desmet, V. Hepatology (1996) [Pubmed]
  5. Heparan sulfate proteoglycan 2 polymorphism in Alzheimer's disease and correlation with neuropathology. Iivonen, S., Helisalmi, S., Mannermaa, A., Alafuzoff, I., Lehtovirta, M., Soininen, H., Hiltunen, M. Neurosci. Lett. (2003) [Pubmed]
  6. Evidence for a role of phospholipase C-gamma1 in the pathogenesis of bipolar disorder. Turecki, G., Grof, P., Cavazzoni, P., Duffy, A., Grof, E., Ahrens, B., Berghöfer, A., Müller-Oerlinghausen, B., Dvoráková, M., Libigerová, E., Vojtechovský, M., Zvolský, P., Joober, R., Nilsson, A., Prochazka, H., Licht, R.W., Rasmussen, N.A., Schou, M., Vestergaard, P., Holzinger, A., Schumann, C., Thau, K., Rouleau, G.A., Alda, M. Mol. Psychiatry (1998) [Pubmed]
  7. Tradeoffs between stereopsis and proximity luminance covariance as determinants of perceived 3D structure. Dosher, B.A., Sperling, G., Wurst, S.A. Vision Res. (1986) [Pubmed]
  8. Heparan sulfate proteoglycans recognize ghost Pick bodies. Odawara, T., Iseki, E., Li, F., Kosaka, K., Ikeda, K. Neurosci. Lett. (1998) [Pubmed]
  9. PLC or TLC: Is outpatient commitment the/an answer? Wales, H.W., Hiday, V.A. International journal of law and psychiatry (2006) [Pubmed]
  10. Dyssegmental dysplasia, Silverman-Handmaker type, is caused by functional null mutations of the perlecan gene. Arikawa-Hirasawa, E., Wilcox, W.R., Le, A.H., Silverman, N., Govindraj, P., Hassell, J.R., Yamada, Y. Nat. Genet. (2001) [Pubmed]
  11. Perlecan is essential for cartilage and cephalic development. Arikawa-Hirasawa, E., Watanabe, H., Takami, H., Hassell, J.R., Yamada, Y. Nat. Genet. (1999) [Pubmed]
  12. An association study of a polymorphism in the heparan sulfate proteoglycan gene (perlecan, HSPG2) and Alzheimer's disease. Rosenmann, H., Meiner, Z., Kahana, E., Aladjem, Z., Friedman, G., Ben-Yehuda, A., Grenader, T., Wertman, E., Abramsky, O. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2004) [Pubmed]
  13. Perlecan knockdown in metastatic prostate cancer cells reduces heparin-binding growth factor responses in vitro and tumor growth in vivo. Savorè, C., Zhang, C., Muir, C., Liu, R., Wyrwa, J., Shu, J., Zhau, H.E., Chung, L.W., Carson, D.D., Farach-Carson, M.C. Clin. Exp. Metastasis (2005) [Pubmed]
  14. Heparan sulfate proteoglycans play a dual role in regulating fibroblast growth factor-2 mitogenic activity in human breast cancer cells. Delehedde, M., Deudon, E., Boilly, B., Hondermarck, H. Exp. Cell Res. (1996) [Pubmed]
  15. Basement membrane-type heparan sulfate proteoglycan (perlecan) and low-density lipoprotein (LDL) are co-localized in granulation tissues: a possible pathogenesis of cholesterol granulomas in jaw cysts. Yamazaki, M., Cheng, J., Hao, N., Takagi, R., Jimi, S., Itabe, H., Saku, T. J. Oral Pathol. Med. (2004) [Pubmed]
  16. Role of heparan sulfate proteoglycan (syndecan-1) on the renal epithelial cells during calcium oxalate monohydrate crystal attachment. Chikama, S., Iida, S., Inoue, M., Kawagoe, N., Tomiyasu, K., Matsuoka, K., Noda, S., Takazono, I. The Kurume medical journal. (2002) [Pubmed]
  17. Structural characterization of the complete human perlecan gene and its promoter. Cohen, I.R., Grässel, S., Murdoch, A.D., Iozzo, R.V. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  18. Distinct evolution of the human carcinoma-associated transmembrane mucins, MUC1, MUC4 AND MUC16. Duraisamy, S., Ramasamy, S., Kharbanda, S., Kufe, D. Gene (2006) [Pubmed]
  19. 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. Dodge, G.R., Kovalszky, I., Chu, M.L., Hassell, J.R., McBride, O.W., Yi, H.F., Iozzo, R.V. Genomics (1991) [Pubmed]
  20. Antiangiogenic antithrombin down-regulates the expression of the proangiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells. Zhang, W., Chuang, Y.J., Swanson, R., Li, J., Seo, K., Leung, L., Lau, L.F., Olson, S.T. Blood (2004) [Pubmed]
  21. Not all perlecans are created equal: interactions with fibroblast growth factor (FGF) 2 and FGF receptors. Knox, S., Merry, C., Stringer, S., Melrose, J., Whitelock, J. J. Biol. Chem. (2002) [Pubmed]
  22. Perlecan up-regulation of FRNK suppresses smooth muscle cell proliferation via inhibition of FAK signaling. Walker, H.A., Whitelock, J.M., Garl, P.J., Nemenoff, R.A., Stenmark, K.R., Weiser-Evans, M.C. Mol. Biol. Cell (2003) [Pubmed]
  23. The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases. Whitelock, J.M., Murdoch, A.D., Iozzo, R.V., Underwood, P.A. J. Biol. Chem. (1996) [Pubmed]
  24. Ultroser G and brain extract induce a continuous basement membrane with specific synaptic elements in aneurally cultured human skeletal muscle cells. van Kuppevelt, T.H., Benders, A.A., Versteeg, E.M., Veerkamp, J.H. Exp. Cell Res. (1992) [Pubmed]
  25. Calcium signaling in human airway goblet cells following purinergic activation. Rossi, A.H., Salmon, W.C., Chua, M., Davis, C.W. Am. J. Physiol. Lung Cell Mol. Physiol. (2007) [Pubmed]
  26. Endorepellin causes endothelial cell disassembly of actin cytoskeleton and focal adhesions through alpha2beta1 integrin. Bix, G., Fu, J., Gonzalez, E.M., Macro, L., Barker, A., Campbell, S., Zutter, M.M., Santoro, S.A., Kim, J.K., Höök, M., Reed, C.C., Iozzo, R.V. J. Cell Biol. (2004) [Pubmed]
  27. Phospholipase C release of basic fibroblast growth factor from human bone marrow cultures as a biologically active complex with a phosphatidylinositol-anchored heparan sulfate proteoglycan. Brunner, G., Gabrilove, J., Rifkin, D.B., Wilson, E.L. J. Cell Biol. (1991) [Pubmed]
  28. The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7. Mongiat, M., Taylor, K., Otto, J., Aho, S., Uitto, J., Whitelock, J.M., Iozzo, R.V. J. Biol. Chem. (2000) [Pubmed]
  29. Immunolocalization of a fibronectin-binding proteoglycan (PG-P1) immunologically related to HSPG2/perlecan in normal and fibrotic human liver. Takahashi, T., Isemura, M., Nakamura, T., Matsui, S., Oyanagi, Y., Asakura, H. J. Hepatol. (1994) [Pubmed]
  30. The N-terminal globular domain of the laminin alpha1 chain binds to alpha1beta1 and alpha2beta1 integrins and to the heparan sulfate-containing domains of perlecan. Ettner, N., Göhring, W., Sasaki, T., Mann, K., Timpl, R. FEBS Lett. (1998) [Pubmed]
  31. The leucine-rich repeat protein PRELP binds perlecan and collagens and may function as a basement membrane anchor. Bengtsson, E., Mörgelin, M., Sasaki, T., Timpl, R., Heinegård, D., Aspberg, A. J. Biol. Chem. (2002) [Pubmed]
  32. Glycosaminoglycans modulate fibronectin matrix assembly and are essential for matrix incorporation of tenascin-C. Chung, C.Y., Erickson, H.P. J. Cell. Sci. (1997) [Pubmed]
  33. Expression of fibroblast growth factor receptor genes in human hepatoma-derived cell lines. Asada, N., Tanaka, Y., Hayashido, Y., Toratani, S., Kan, M., Kitamoto, M., Nakanishi, T., Kajiyama, G., Chayama, K., Okamoto, T. In Vitro Cell. Dev. Biol. Anim. (2003) [Pubmed]
  34. PDGF stimulation of inositol phospholipid hydrolysis requires PLC-gamma 1 phosphorylation on tyrosine residues 783 and 1254. Kim, H.K., Kim, J.W., Zilberstein, A., Margolis, B., Kim, J.G., Schlessinger, J., Rhee, S.G. Cell (1991) [Pubmed]
  35. Perlecan inhibits smooth muscle cell adhesion to fibronectin: role of heparan sulfate. Lundmark, K., Tran, P.K., Kinsella, M.G., Clowes, A.W., Wight, T.N., Hedin, U. J. Cell. Physiol. (2001) [Pubmed]
  36. Expression of the basement membrane heparan sulfate proteoglycan (perlecan) in human synovium and in cultured human synovial cells. Dodge, G.R., Boesler, E.W., Jimenez, S.A. Lab. Invest. (1995) [Pubmed]
  37. Lipoprotein modulation of subendothelial heparan sulfate proteoglycans (perlecan) and atherogenicity. Pillarisetti, S. Trends Cardiovasc. Med. (2000) [Pubmed]
  38. Perlecan mediates the antiproliferative effect of apolipoprotein E on smooth muscle cells. An underlying mechanism for the modulation of smooth muscle cell growth? Paka, L., Goldberg, I.J., Obunike, J.C., Choi, S.Y., Saxena, U., Goldberg, I.D., Pillarisetti, S. J. Biol. Chem. (1999) [Pubmed]
  39. Characterization of a conduit system containing laminin-5 in the human thymus: a potential transport system for small molecules. Drumea-Mirancea, M., Wessels, J.T., Müller, C.A., Essl, M., Eble, J.A., Tolosa, E., Koch, M., Reinhardt, D.P., Sixt, M., Sorokin, L., Stierhof, Y.D., Schwarz, H., Klein, G. J. Cell. Sci. (2006) [Pubmed]
  40. Heparan sulfate proteoglycans mediate a potent inhibitory signal for migration of vascular smooth muscle cells. Koyama, N., Kinsella, M.G., Wight, T.N., Hedin, U., Clowes, A.W. Circ. Res. (1998) [Pubmed]
  41. A protective role for kidney apolipoprotein E. Regulation of mesangial cell proliferation and matrix expansion. Chen, G., Paka, L., Kako, Y., Singhal, P., Duan, W., Pillarisetti, S. J. Biol. Chem. (2001) [Pubmed]
  42. Expression of proteoglycan core proteins in human bone marrow stroma. Schofield, K.P., Gallagher, J.T., David, G. Biochem. J. (1999) [Pubmed]
  43. CTGF/Hcs24, hypertrophic chondrocyte-specific gene product, interacts with perlecan in regulating the proliferation and differentiation of chondrocytes. Nishida, T., Kubota, S., Fukunaga, T., Kondo, S., Yosimichi, G., Nakanishi, T., Takano-Yamamoto, T., Takigawa, M. J. Cell. Physiol. (2003) [Pubmed]
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