Normal labor associated with changes in uterine heparan sulfate proteoglycan expression and localization
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Perlecan
Expression (computer science)
Perlecan
Versican
Biglycan
Syndecan 1
Dermatan sulfate
Chondroitin sulfate proteoglycan
Heparanase
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Perlecan is a heparan sulfate proteoglycan and a major component of the glomerular basement membrane. To understand the role of heparan sulfate chains of perlecan in glomerular filtration, detailed analyses were performed of the kidneys of Hspg2(Delta)(3/)(Delta)(3) mice, whose perlecan lacks heparan sulfate attachment sites in N-terminal domain I. Macroscopic, histologic, and electron microscopic observations, as well as immunohistochemical and immunoelectron microscopic analyses using specific antibodies against perlecan and agrin core proteins, revealed no significant abnormalities in these mice under physiologic conditions. Polyethyleneimine staining demonstrated no significant changes in charge density in the glomerular basement membrane. Transcripts of other heparan sulfate proteoglycans, agrin, and collagen type XVIII, as well as perlecan, were expressed at similar levels to those in the wild-type littermates. Approximately 40% of the perlecan synthesized by Hspg2(Delta)(3/)(Delta)(3) fibroblasts was substituted with heparin sulfate and 60% was substituted with chondroitin sulfate. All of the perlecan synthesized by wild-type fibroblasts contained heparin sulfate, indicating an altered substitution of glycosaminoglycans on Hspg2(Delta)(3/)(Delta)(3) perlecan. Immunostaining indicated that the level of chondroitin sulfate was actually increased in the Hspg2(Delta)(3/)(Delta)(3) glomerular basement membrane. When administered intraperitoneally with BSA, Hspg2(Delta)(3/)(Delta)(3) mice exhibited remarkable proteinuria. These findings suggest that heparan sulfate chains of perlecan play an important role in glomerular filtration, especially of a large amount of protein.
Perlecan
Agrin
Chondroitin sulfate proteoglycan
Type IV collagen
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Perlecan
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Perlecan
Heparanase
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Perlecan is primarily a heparan sulfate containing proteoglycan found in all basement membranes. Rotary shadowed images of perlecan show it to contain three glycosaminoglycan (GAG) side chains extending from one end of its core protein. Domain I is at the N terminus of perlecan and contains three closely spaced Ser-Gly-Asp sequences that may serve in GAG attachment. We evaluated the serines in these three sequences for GAG attachment by preparing a cDNA construct encoding for the N-terminal half (domains I, II, and III) of perlecan and then a series of constructs containing deletions and mutations within domain I of the domain I/II/III construct, expressing these constructs in COS-7 cells, and then analyzing the recombinant product for GAG side chains and GAG type. The results showed that all three serine residues in the Ser-Gly-Asp sequences in domain I can accept both chondroitin and heparan sulfate side chains but that a cluster of acidic residues N-terminal to these sequences is the primary determinant responsible for targeting these sites for heparan sulfate. Furthermore, there are two elements that can enhance heparan sulfate synthesis at a targeted site: 1) the presence of a the SEA module in the C-terminal region of domain I and 2) the presence of multiple acceptors in close proximity. These results indicate that the proportion of heparan and chondroitin sulfate at any one site in domain I of perlecan is regulated by multiple factors. Perlecan is primarily a heparan sulfate containing proteoglycan found in all basement membranes. Rotary shadowed images of perlecan show it to contain three glycosaminoglycan (GAG) side chains extending from one end of its core protein. Domain I is at the N terminus of perlecan and contains three closely spaced Ser-Gly-Asp sequences that may serve in GAG attachment. We evaluated the serines in these three sequences for GAG attachment by preparing a cDNA construct encoding for the N-terminal half (domains I, II, and III) of perlecan and then a series of constructs containing deletions and mutations within domain I of the domain I/II/III construct, expressing these constructs in COS-7 cells, and then analyzing the recombinant product for GAG side chains and GAG type. The results showed that all three serine residues in the Ser-Gly-Asp sequences in domain I can accept both chondroitin and heparan sulfate side chains but that a cluster of acidic residues N-terminal to these sequences is the primary determinant responsible for targeting these sites for heparan sulfate. Furthermore, there are two elements that can enhance heparan sulfate synthesis at a targeted site: 1) the presence of a the SEA module in the C-terminal region of domain I and 2) the presence of multiple acceptors in close proximity. These results indicate that the proportion of heparan and chondroitin sulfate at any one site in domain I of perlecan is regulated by multiple factors.
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Although interleukin‐2 (IL‐2) is typically considered a soluble cytokine, our laboratory has shown that the availability of IL‐2 in lymphoid tissues is regulated, in part, by an association with heparan sulfate glycosaminoglycan. Heparan sulfate is usually found in proteoglycan form, in which the heparan sulfate chains are covalently linked to a specific core protein. We now show that perlecan is one of the major IL‐2‐binding heparan sulfate proteoglycans in murine spleen. IL‐2 binds perlecan via heparan sulfate chains, as enzymatic removal of heparan sulfate from splenic perlecan abolishes its ability to bind IL‐2. Furthermore, we demonstrate that perlecan‐bound IL‐2 supports the proliferation of an IL‐2‐dependent cell line. Identification of perlecan as a major heparan sulfate proteoglycan that binds IL‐2 has implications for both the localization and regulation of IL‐2 in vivo .
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Syndecan 1
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Heparan sulfate proteoglycan(HSPG) is a glycoconjugate composed of core protein to which heparan sulfate chains are attached.They are widely distributed on the cell membrane and extracellular matrix.Syndecans and glypicans are the main heparan sulfate proteoglycan located on the cell membrane,while perlecan and agrin are the most investigated heparan sulfate proteoglycan in the extracellular matrix.They play an important role during physiological and pathological conditions including development,wound healing,cancer development,infection, immune response.Their function can be attributed to both the core protein and the attached heparan sulfate chains. In this review,we would like to summarize the recent progress of the heparan sulfate proteoglycan research.In the meantime,we will also highlight the potential of heparan sulfate proteoglycan as target for drug discovery development and marker for clinical diagnostics.
Perlecan
Syndecan 1
Agrin
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Perlecan
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Perlecan, a heparan sulfate proteoglycan, is widely distributed in developing and adult tissues and plays multiple, important physiological roles. Studies with knockout mouse models indicate that expression of perlecan and heparan sulfate is critical for proper skeletal morphogenesis. Heparan sulfate chains bind and potentiate the activities of various growth factors such as fibroblast growth factor 2 (FGF-2). Previous studies indicate that important biological activities are associated with the heparan sulfate-bearing domain I of perlecan (PlnDI; French et al. J. Bone Miner. Res. 17 , 48, 2002). In the present study, we have used recombinant, glycosaminoglycan-bearing PlnDI to reconstitute three-dimensional scaffolds of collagen I. Collagen I fibrils bound PlnDI much better than native collagen I monomers or heat-denatured collagen I preparations. Heparitinase digestion demonstrated that recombinant PlnDI was substituted with heparan sulfate and that these heparan sulfate chains were critically important not only for efficient integration of PlnDI into scaffolds, but also for FGF-2 binding and retention. PlnDI-containing collagen I scaffolds to which FGF-2 was bound sustained growth of both MG63, an osteoblastic cell line, and human bone marrow stromal cells (hBMSCs) significantly better than scaffolds lacking either PlnDI or FGF-2. Collectively, these studies demonstrate the utility of PlnDI in creating scaffolds that better mimic natural extracellular matrices and better support key biological activities.
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