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

• An association study of a polymorphism in the heparan sulfate proteoglycan gene (perlecan, HSPG2) and Alzheimer's disease [12].
• Perlecan knockdown in metastatic prostate cancer cells reduces heparin-binding growth factor responses in vitro and tumor growth in vivo [13].
• To investigate the potential regulation of FGF-2 mitogenic activity by heparan sulfate proteoglycans (HSPG), we have treated human breast cancer cells by glycosaminoglycan degrading enzymes or a metabolic inhibitor of proteoglycan sulfation: sodium chlorate [14].
• 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 [15].
• We have reported that heparan sulfate (HS)/heparan sulfate proteoglycan (HSPG, syndecan-1) expression significantly increased in the rat kidney during calcium oxalate (CaOx) nephrolithiasis [16].

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

• Southern blot analyses of DNA from 120 human/rodent somatic cell hybrids, including subclones with specific translocations or spontaneous breaks of human chromosome 1, demonstrated the presence of HSPG2 gene on the telomeric region of the short arm of chromosome 1 (1p34-pter) [19].
• Antiangiogenic antithrombin down-regulates the expression of the proangiogenic heparan sulfate proteoglycan, perlecan, in endothelial cells [20].
• Interestingly, perlecan isolated from a colon carcinoma cell line that was capable of binding FGF-2 was incapable of activating any BaF3 cell line unless the HS was removed from the protein core [21].
• Human basement membrane heparan sulfate proteoglycan (HSPG) perlecan binds and activates fibroblast growth factor (FGF)-2 through its heparan sulfate (HS) chains [21].
• We previously reported that fully assembled basement membranes are nonpermissive to smooth muscle cell (SMC) replication and that perlecan (PN), a basement membrane heparan sulfate proteoglycan, is a dominant effector of this response [22].

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

• The protein core of the proteoglycan perlecan binds specifically to fibroblast growth factor-7 [28].
• Immunolocalization of a fibronectin-binding proteoglycan (PG-P1) immunologically related to HSPG2/perlecan in normal and fibrotic human liver [29].
• 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 [30].
• The leucine-rich repeat protein PRELP binds perlecan and collagens and may function as a basement membrane anchor [31].
• The perlecan binding site in tenascin-C was mapped to the fibronectin type III domains 3-5, but this binding was strongly enhanced for the small splice variant, which is the major form incorporated into the matrix [32].

Enzymatic interactions of HSPG2

• Down-regulation of perlecan expression by cleaved and latent antithrombins was observed in both basic fibroblast growth factor (bFGF)-stimulated and unstimulated cells, whereas the antiangiogenic antithrombins inhibited the proliferation of only bFGF-stimulated HUVECs by arresting cells at the G(1) cell cycle phase [20].

Regulatory relationships of HSPG2

• An RT-PCR analysis revealed that all cell lines except PLC/PRF/5 expressed all FGFR mRNAs: FGF-R1 (IIIc), -R2 (IIIb), -R2 (IIIc), -R3 (IIIb), -R3 (IIIc), and -R4 mRNAs [33].
• Also, PDGF induces an increase in the hydrolysis of inositol phospholipids by PLC [34].
• Perlecan inhibits smooth muscle cell adhesion to fibronectin: role of heparan sulfate [35].
• Moreover, the perlecan core protein was shown to be up-regulated by TGF-beta and down-regulated by basic FGF [36].
• Atherogenic levels of low-density lipoprotein (LDL), oxidized LDL and lysolecithin decrease not only perlecan core protein synthesis but also enhance heparan sulfate degradation by stimulating endothelial secretion of heparanase [37].

Other interactions of HSPG2

• These results show that cultured human HSC can synthesize all four syndecans, glypican, and perlecan [4].
• Perlecan mediates the antiproliferative effect of apolipoprotein E on smooth muscle cells. An underlying mechanism for the modulation of smooth muscle cell growth [38]?
• The degradation of human endothelial cell-derived perlecan and release of bound basic fibroblast growth factor by stromelysin, collagenase, plasmin, and heparanases [23].
• In this report we examined the specific binding of FGF7 to various domains and subdomains of perlecan protein core [28].
• Using high-resolution light microscopy, we show here that LN-5 is localized in a bi-membranous conduit-like structure, together with other typical basement membrane components including collagen type IV, nidogen and perlecan [39].

Analytical, diagnostic and therapeutic context of HSPG2

• The impact of HSPG2 polymorphism on beta amyloid and tau pathology was studied using immunohistochemistry [5].
• Northern blot analysis revealed that PDGF-AA increased syndecan-1 mRNA expression more than did PDGF-BB, whereas both PDGF isoforms decreased perlecan expression [40].
• Because the loss of anionic HSPG in the basement membrane and mesangial matrix is associated with disruption of filtration barrier, these data suggest a novel role for kidney apoE in preserving the filtration barrier [41].
• The core proteins were detected by Western blotting using antibodies directed against syndecans-1-4, glypican-1 and the ECM HSPG, perlecan [42].
• An immunofluorescence study showed that CTGF/Hcs24 was colocalized with heparan sulfate and perlecan in human chondrosarcoma-derived chondrocytic cell line HCS-2/8 in vitro [43].

References