Disease relevance of Hspg2

• In both tumor xenografts induced by human colon carcinoma cells and tumor allografts induced by highly invasive mouse melanoma cells, perlecan suppression caused substantial inhibition of tumor growth and neovascularization [1].
• To test this hypothesis, we first studied perlecan regulation in mice after inflammation induced by a brain stab wound [2].
• Expression of perlecan proteoglycan in the infarct zone of mouse myocardial infarction [3].
• Increased intimal hyperplasia and smooth muscle cell proliferation in transgenic mice with heparan sulfate-deficient perlecan [4].
• We have previously shown that Pseudomonas aeruginosa, through its virulence factor LasA, enhances the in vitro shedding of syndecan-1-the predominant cell-surface HSPG of epithelia [5].

Psychiatry related information on Hspg2

• It is also possible that a similar increased expression of perlecan in neurons and reactive astrocytes could occur in humans following neuronal injury, which could be a source of perlecan, in senile plaques of Alzheimer's disease [6].

High impact information on Hspg2

• Syndecan-1 is a cell-surface, heparan-sulphate proteoglycan (HSPG) predominantly expressed by epithelial cells [7].
• Through the generation of AAV2-AAV8 hybrids and the creation of site-directed mutations, we mapped the domain that directs the activation of T cells to the RXXR motif on VP3, which was previously shown to confer binding of the virion to heparan sulfate proteoglycan (HSPG) [8].
• Heparan sulphate, or the heparan sulphate proteoglycan perlecan, has been identified in all amyloids and implicated in the earliest stages of inflammation-associated (AA) amyloid induction [9].
• Here we show that perlecan, a multifunctional heparan sulfate proteoglycan concentrated at the NMJ, is the unique acceptor molecule for collagen-tailed AChE at sites of nerve-muscle contact and is the principal mechanism for localizing AChE to the synaptic basal lamina [10].
• Absence of acetylcholinesterase at the neuromuscular junctions of perlecan-null mice [10].

Chemical compound and disease context of Hspg2

• The results indicate that the endogenous HS side-chains of perlecan contribute to SMC growth control both in vitro and during intimal hyperplasia, possibly by sequestering heparin-binding mitogens such as FGF-2 [4].
• Hepatoma (HepG2) cells and endothelial cells cultured in high glucose also showed decreased sulfate and glucosamine incorporation into HSPG [11].
• Previously, a cellular UDP-Glc deficiency was related with a hypersensitivity to the cytotoxic effect of Cp-PLC [12].
• Through this work we identified a number of novel target genes for the WT1 transcription factor, including uvomorulin, integrin alpha8 and perlecan, and suggest that WTI may activate the IGF-II gene, also implicated in the development of Wilms' tumor [13].
• The development of histological lesions, proteinuria, hypertension, accumulation of collagens I, III, and IV, laminin, and HSPG in the renal cortex of NZB/W F1 mice were suppressed by FR139317 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)[14]

Biological context of Hspg2

• Expression of the heparan sulfate proteoglycan, perlecan, during mouse embryogenesis and perlecan chondrogenic activity in vitro [15].
• Impaired angiogenesis, delayed wound healing and retarded tumor growth in perlecan heparan sulfate-deficient mice [16].
• Addition of Pl-PLC to sparsely seeded vascular endothelial cells resulted in a marked stimulation of cell proliferation, but there was no mitogenic effect of Pl-PLC on 3T3 fibroblasts [17].
• This type of binding is consistent with the involvement HSPG-mediated endocytosis [18].
• Here, we report the crystal structure of the mouse nidogen-1 G2 fragment, which contains binding sites for collagen IV and perlecan [19].

Anatomical context of Hspg2

• Nidogen and perlecan are large multifunctional basement membrane (BM) proteins conserved in all metazoa [20].
• Heparan sulfate proteoglycans (HSPG) have been shown to be involved in the activation of tyrosine kinase receptors by basic fibroblasts growth factor (bFGF), a strong inhibitor of skeletal muscle differentiation [21].
• In this study we evaluated the expression and localization of perlecan during differentiation of C2C12 skeletal muscle cells [21].
• Immunocytolocalization studies indicate that perlecan is localized on the myoblast surface and by immunogold staining we have demonstrated that it is associated with patches of incipient extracellular matrix [21].
• By immunofluorescence microscopy almost no perlecan staining associated with the surface of myotubes was observed [21].

Associations of Hspg2 with chemical compounds

• The HS at the NH(2) terminus of perlecan was removed while the core protein remained intact [16].
• The expression of perlecan mRNA decreased substantially during skeletal muscle differentiation, in contrast to the increase in transcripts for specific skeletal muscle proteins such as myogenin and creatine kinase [21].
• Blot overlay assays have shown that perlecan binds alpha-DG in a calcium and heparin-sensitive manner [22].
• The loss of the basement membrane proteoglycan perlecan and the podocyte protein nephrin in the diabetic state was not prevented in the PKC-beta(-/-) mice as previously demonstrated in the nonalbuminuric diabetic PKC-alpha(-/-) mice [23].
• By 7 weeks, only animals infused with A beta plus HSPG demonstrated compaction of the Congo red material from amorphous, wispy deposits (at 1 week) to stellate deposits resembling a Maltese cross [24].

Physical interactions of Hspg2

• This competition may result in the presentation of perlecan-bound growth factors such as HB-GAM to effect synaptic induction [22].
• Crystal structure and mutational analysis of a perlecan-binding fragment of nidogen-1 [19].
• Perlecan is a specific proteoglycan that binds to amyloid precursor protein and beta-amyloid peptide, is present within amyloid deposits, and has been implicated in plaque formation [2].
• These results suggest that dystroglycan is essential for the assembly of a synaptic basement membrane, most notably by localizing AChE through its binding to perlecan [25].
• In the present study we investigated the effect of the isoform and the amount of apoE per particle, as well as the role of LPL on the binding of beta-VLDL to HSPG [26].

Co-localisations of Hspg2

• In Xenopus muscle cells, the cell-surface perlecan is precisely colocalized with DG [22].

Regulatory relationships of Hspg2

• The binding of beta-VLDL to heparan sulfate proteoglycans (HSPG) has been reported to be stimulated by both apoE and lipoprotein lipase (LPL) [26].

Other interactions of Hspg2

• We have solved the crystal structure at 2.0 A resolution of the mouse nidogen-1 G2-perlecan IG3 complex [20].
• Both stimulatory and inhibitory effects of perlecan on FGF-2 signaling have been reported [16].
• However, at 24 weeks and in the LDL receptor heterozygous background, the presence of a perlecan knockout allele did not significantly alter lesion size [27].
• Most notably, HIP/RPL29 accumulated in decidua, where it displayed a pattern complementary to that of pericellular deposition of the HS proteoglycan, perlecan [28].
• Furthermore, perlecan is present in muscle lysate immunoprecipitated with an anti-DG antibody [22].

Analytical, diagnostic and therapeutic context of Hspg2

• To understand the in vivo function of HS carried by perlecan, the perlecan gene heparan sulfate proteoglycan 2 (Hspg2) was mutated in mouse by gene targeting [16].
• Analysis of the core protein of the HSPG immunoprecipitated from [35S]methionine-labeled C2C12 after treatment with heparitinase revealed two polypeptides of 170 and over 300 kDa [21].
• Site-directed mutagenesis demonstrates that the conserved residues are involved in perlecan binding [19].
• To test our hypothesis that perlecan is increased in the myocardial infarct zone, we examined perlecan expression after experimentally induced myocardial infarction in BALb/c mice by the methods of in situ hybridization, Northern blotting, and immunohistochemistry [3].
• In situ hybridization revealed mRNA signals for perlecan in the infarct marginal zone on day 2 and in the infarct interior zone around infarct granulation tissue on day 7 [3].

References