Lysosomal Degradation of Heparin and Heparan Sulphate

Freeman, Craig; Hopwood, John J.

doi:10.1007/978-1-4899-2444-5_13

Cited by 41 publications

(25 citation statements)

References 38 publications

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“…While sulfamidases have been implicated in HS metabolism, these enzymes seem to act in an exolytic fashion, at the nonreducing terminus of the chain (51). No endoenzyme of the type required to generate the JM-403 epitope has yet been described.…”

Section: Discussionmentioning

confidence: 99%

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Born

Gunnarsson

Bakker

et al. 1995

Journal of Biological Chemistry

138

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Proteoglycans consist of one or more glycosaminoglycan side chains covalently bound to a core protein (1, 2). The heparan sulfate proteoglycans (HSPGs) 1 constitute a major class of proteoglycans that are found in the extracellular matrix, especially in basement membranes, and at the cell surface, associated with the cell membrane (3-5). Many biological activities of HSPGs are due to interactions between the heparan sulfate (HS) polysaccharide side chains and a variety of proteins, which include extracellular matrix molecules, enzymes, enzyme inhibitors, growth factors and other cytokines (2, 5-7). These interactions can be specific, dependent on defined sulfation patterns within given sequences of sugar residues, as described for antithrombin (8), basic fibroblast growth factor (9, 10), and hepatocyte growth factor (11); others appear to be mainly based on relatively nonspecific electrostatic interactions, and involve proteins such as lipoprotein lipase (12), platelet factor 4 (13) and mast cell protease I (14) (for a general discussion, see Ref. 15).The biosynthesis of HS involves the formation of a nonsulfated (GlcA␤1,4-GlcNAc␣1,4) n precursor polysaccharide, which subsequently undergoes a series of polymer-modification reactions. These reactions start with N-deacetylation/N-sulfation of GlcNAc residues, which is followed by C-5 epimerization of GlcA to iduronic acid (IdoA) units, and finally by O-sulfation at various positions (5). The GlcA C-5 epimerization and O-sulfation reactions occur in the close vicinity of N-sulfate groups, pointing to a key role for the glucosaminyl N-deacetylase/ N-sulfotransferase enzyme in determining the overall extent of modification of the HS chain. Structural analysis of HS preparations have revealed that the modifications tend to colocalize in block sequences, separated by relatively unmodified domains (16 -19). The extent of biosynthetic modification, affecting the number, length, and substitution patterns of the modified domains as well as their position along the HS chain, may differ among cell types (20), alter during proliferation (21), and change as a result of cell transformation (22,23). Structural analysis of HS is complicated by the fact that even highly purified and uniform preparations consist of mixtures of polysaccharide chains that have reached different levels of modification. Monoclonal antibodies (mAbs) that specifically recognize well defined epitopes in HS could be major tools in such analysis. We recently described the production of such an an-

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Section: Discussionmentioning

confidence: 99%

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Born

Gunnarsson

Bakker

et al. 1995

Journal of Biological Chemistry

138

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“…The purported functions of these genes seem to be related to some of the histopathologic changes that occur in the aging rat VP. For example, iduronate 2-sulfatase is a lysosomal enzyme (Froissart et al, 1995) that plays a major role in the breakdown of glycosaminoglycans, particularly heparan sulfate and dermatan sulfate, in the extracellular matrix (Freeman and Hopwood, 1992). An increase in iduronate 2-sulfatase expression in the VPs of aged rats may be related to a faster degradation of extracellular matrix mucopolysaccharides, possibly connected to prostatic atrophy in the senescent rats.…”

Section: Lau Et Almentioning

confidence: 99%

Age-Associated Changes in Histology and Gene-Expression Profile in the Rat Ventral Prostate

Lau

Tam

Thompson

et al. 2003

Laboratory Investigation

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SUMMARY:The incidence of prostate diseases rises dramatically with age in men, yet little is understood of the mechanisms underlying prostatic senescence and its contribution to disease development in the gland. In Noble rats, aging of the ventral prostate (VP) is characterized morphologically by widespread atrophy of acini, increased accumulation of concretions in glandular lumen, infiltration of inflammatory cells, and focal epithelial atypia. We used a cDNA microarray containing 2388 known transcripts, together with the Tyramide Amplification System and t statistics, to identify differentially expressed genes in the VPs of young (3 months old) and old (16 months old) rats. A total of 78 VP genes were found to be differentially expressed by the two groups; in old rats, 65 VP genes (83%) showed reduced expression and 13 genes (17%) showed increased expression compared with young animals. The age-dependent underexpressed genes fell into several functional clusters: those involved in amino-acid metabolism, protein synthesis, protein secretion and degradation, vesicle/membrane trafficking, energy metabolism, signal transduction, spermidine and spermine syntheses, and cellular defense against stress. The overexpressed genes included iduronate 2-sulfatase, HLA class I locus C heavy chain, membrane cofactor protein of the complement system, TRPM-2, cadherin-associated protein-related, and X-CGD. Post hoc analyses confirmed a progressive decline in the expression of ribophorin II and BiP and a gradual increase in the expression of TRPM-2 in rat VPs as animals aged from 3 to 19 months old. In conclusion, the observed widespread declines in expression of genes involved in protein synthesis, protein fidelity maintenance, anabolism, growth inhibition, and energy metabolism, together with increased expression of genes implicated in cell survival in the VPs of senescent rats, may help explain the susceptibility of the prostates of elderly men to development of disease. (Lab Invest 2003, 83:743-757).

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“…Pulse-Chase Experiments-Both wild-type CHO and mutant pgsF-17 cells were grown to near confluence and pulse-labeled for 1 h with 100 Ci/ml Na 35 SO 4 (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40) Ci/mg; NEN Life Science Products) in sulfate free F-12 medium. After removing the labeled medium, the cell layers were washed three times, and fresh F-12 medium supplemented with 1 mM Na 2 SO 4 was added.…”

Section: Methodsmentioning

confidence: 99%

Turnover of Heparan Sulfate Depends on 2-O-Sulfation of Uronic Acids

Bai

Bame²,

Habuchi³

et al. 1997

Journal of Biological Chemistry

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To study how the pattern of sulfation along a heparan sulfate chain affects its turnover, we examined heparan sulfate catabolism in wild-type Chinese hamster ovary cells and mutant pgsF-17, defective in 2-O-sulfation of uronic acid residues (Bai, X., and Esko, J. D. (1996) J. Biol. Chem. 271, 17711-17717). Heparan sulfate from the mutant contains normal amounts of 6-O-sulfated glucosamine residues and iduronic acid and somewhat higher levels of N-sulfated glucosamine residues but lacks any 2-O-sulfated iduronic or glucuronic acid residues. Pulse-chase experiments showed that both mutant and wild-type cells transport newly synthesized heparan sulfate proteoglycans to the plasma membrane, where they shed into the medium or move into the cell through endocytosis. Internalization of the cell-associated molecules leads to sequential endoglycosidase (heparanase) fragmentation of the chains and eventual lysosomal degradation. In wild-type cells, the chains begin to degrade within 1 h, leading to the accumulation of intermediate (10 -20-kDa) and small (4 -7-kDa) oligosaccharides. Mutant cells did not generate these intermediates, although internalization and intracellular trafficking of the heparan sulfate chains appeared normal, and the chains degraded with normal kinetics. This difference was not due to defective heparanase activities in the mutant, since cytoplasmic extracts from mutant cells cleaved wild-type heparan sulfate chains in vitro. Instead, the heparan sulfate chains from the mutant were relatively resistant to degradation by cellular heparanases. These findings suggest that 2-O-sulfated iduronic acid residues in heparan sulfate are important for cleavage by endogenous heparanases but not for the overall catabolism of the chains.

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Lysosomal Degradation of Heparin and Heparan Sulphate

Cited by 41 publications

References 38 publications

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Presence of N-Unsubstituted Glucosamine Units in Native Heparan Sulfate Revealed by a Monoclonal Antibody

Age-Associated Changes in Histology and Gene-Expression Profile in the Rat Ventral Prostate

Turnover of Heparan Sulfate Depends on 2-O-Sulfation of Uronic Acids

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