Development of Molecules Antagonizing Heparan Sulfate Proteoglycans

2021 ◽  
Vol 47 (03) ◽  
pp. 316-332 ◽  
Author(s):  
Tanja Gerlza ◽  
Christina Trojacher ◽  
Nikola Kitic ◽  
Tiziana Adage ◽  
Andreas J. Kungl
Keyword(s):  
Extracellular Matrix ◽  
Heparan Sulfate ◽  
Cell Communication ◽  
Secretory Vesicle ◽  
Heparan Sulfate Proteoglycans ◽  
Current Status ◽  
Communication Processes ◽  
Membrane Bound ◽  
Chain Lengths ◽  
Cancer And Inflammation

AbstractHeparan sulfate proteoglycans (HSPGs) occur in almost every tissue of the human body and consist of a protein core, with covalently attached glycosaminoglycan polysaccharide chains. These glycosaminoglycans are characterized by their polyanionic nature, due to sulfate and carboxyl groups, which are distributed along the chain. These chains can be modified by different enzymes at varying positions, which leads to huge diversity of possible structures with the complexity further increased by varying chain lengths. According to their location, HSPGs are divided into different families, the membrane bound, the secreted extracellular matrix, and the secretory vesicle family. As members of the extracellular matrix, they take part in cell–cell communication processes on many levels and with different degrees of involvement. Of particular therapeutic interest is their role in cancer and inflammation as well as in infectious diseases. In this review, we give an overview of the current status of medical approaches to antagonize HSPG function in pathology.

Extracellular matrix histone H1 binds to perlecan, is present in regenerating skeletal muscle and stimulates myoblast proliferation

2002 ◽  
Vol 115 (10) ◽  
pp. 2041-2051 ◽  
Author(s):  
Juan Pablo Henriquez ◽  
Juan Carlos Casar ◽  
Luis Fuentealba ◽  
David J. Carey ◽  
Enrique Brandan
Keyword(s):  
Skeletal Muscle ◽  
Extracellular Matrix ◽  
Heparan Sulfate ◽  
Muscle Differentiation ◽  
Histone H1 ◽  
Heparan Sulfate Proteoglycans ◽  
Skeletal Muscle Regeneration ◽  
Proliferative Effect ◽  
Myoblast Proliferation

Heparan sulfate chains of proteoglycans bind to and regulate the function of a wide variety of ligands. In myoblasts, heparan sulfate proteoglycans modulate basic fibroblast growth factor activity and regulate skeletal muscle differentiation. The aim of this study was to identify endogenous extracellular ligands for muscle cell heparan sulfate proteoglycans.[35S]heparin ligand blot assays identified a 33/30 kDa doublet(p33/30) in detergent/high ionic strength extracts and heparin soluble fractions obtained from intact C2C12 myoblasts. p33/30 is localized on the plasma membrane or in the extracellular matrix where its level increases during muscle differentiation. Heparin-agarose-purified p33/30 was identified as histone H1. In vitro binding assays showed that histone H1 binds specifically to perlecan. Immunofluorescence microscopy showed that an extracellular pool of histone H1 colocalizes with perlecan in the extracellular matrix of myotube cultures and in regenerating skeletal muscle. Furthermore, histone H1 incorporated into the extracellular matrix strongly stimulated myoblast proliferation via a heparan-sulfate-dependent mechanism.These results indicate that histone H1 is present in the extracellular matrix of skeletal muscle cells, where it interacts specifically with perlecan and exerts a strong proliferative effect on myoblasts, suggesting a role for histone H1 during skeletal muscle regeneration.

scholarly journals Membrane anchoring of heparan sulfate proteoglycans by phosphatidylinositol and kinetics of synthesis of peripheral and detergent-solubilized proteoglycans in Schwann cells.

1989 ◽  
Vol 108 (5) ◽  
pp. 1891-1897 ◽  
Author(s):  
D J Carey ◽  
D M Evans
Keyword(s):  
Cell Surface ◽  
Heparan Sulfate ◽  
Schwann Cells ◽  
Electrostatic Interactions ◽  
Heparan Sulfate Proteoglycans ◽  
Membrane Bound ◽  
Covalently Linked ◽  
Mode Of Attachment ◽  
Membrane Anchoring ◽  
Kinetics Of

Previous studies have shown that Schwann cells synthesize both peripheral and integral hydrophobic cell surface heparan sulfate proteoglycans (HSPGs). The experiments reported here were undertaken to investigate the mode of attachment of these proteins to the cell surface and their potential interrelationship. The binding of the hydrophobic HSPGs to membranes appears to be via covalently linked phosphatidylinositol based on the observation that incubation of the detergent-solubilized protein with purified phosphatidylinositol-specific phospholipase C significantly reduces the ability of the HSPGs to associate with phospholipid vesicles in a reconstitution assay. The peripherally associated HSPGs were released from the cells by incubation in the presence of heparin (10 mg/ml), 10 mM phytic acid (inositol hexaphosphate), or 2 M NaCl. These treatments also solubilized basement membrane HSPGs synthesized by the Schwann cells. These data suggest that the peripheral HSPGs are bound to the surface by electrostatic interactions. The peripheral and hydrophobic HSPGs were identical in overall size, net charge, length of glycosaminoglycan chains, and patterns of N-sulfation. To determine whether the peripheral HSPGs were derived from the membrane-bound form by cleavage of the membrane anchor, we examined the kinetics of synthesis and degradation of the two forms of HSPGs. The results obtained indicated the existence of two pools of detergent-solubilized HSPG with fast (t1/2 = 6 h) and slow (t1/2 = 55 h) turnover kinetics. The data were consistent with a model in which the peripheral HSPGs were derived from the slowly turning over pool of detergent-solubilized HSPGs.

scholarly journals Heparan sulfate proteoglycans: structure, protein interactions and cell signaling

2009 ◽  
Vol 81 (3) ◽  
pp. 409-429 ◽  
Author(s):  
Juliana L. Dreyfuss ◽  
Caio V. Regatieri ◽  
Thais R. Jarrouge ◽  
Renan P. Cavalheiro ◽  
Lucia O. Sampaio ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cell Signaling ◽  
Heparan Sulfate ◽  
Protein Interactions ◽  
Cellular Signaling ◽  
Structural Characteristics ◽  
Heparan Sulfate Proteoglycans ◽  
Protein Motifs ◽  
Extracellular Matrix Components ◽  
Heparan Sulfates

Heparan sulfate proteoglycans are ubiquitously found at the cell surface and extracellular matrix in all the animal species. This review will focus on the structural characteristics of the heparan sulfate proteoglycans related to protein interactions leading to cell signaling. The heparan sulfate chains due to their vast structural diversity are able to bind and interact with a wide variety of proteins, such as growth factors, chemokines, morphogens, extracellular matrix components, enzymes, among others. There is a specificity directing the interactions of heparan sulfates and target proteins, regarding both the fine structure of the polysaccharide chain as well precise protein motifs. Heparan sulfates play a role in cellular signaling either as receptor or co-receptor for different ligands, and the activation of downstream pathways is related to phosphorylation of different cytosolic proteins either directly or involving cytoskeleton interactions leading to gene regulation. The role of the heparan sulfate proteoglycans in cellular signaling and endocytic uptake pathways is also discussed.

scholarly journals The Role of Glypicans in Cancer Progression and Therapy

2020 ◽  
Vol 68 (12) ◽  
pp. 841-862 ◽  
Author(s):  
Nan Li ◽  
Madeline R. Spetz ◽  
Mitchell Ho
Keyword(s):  
Extracellular Matrix ◽  
Cell Proliferation ◽  
Growth Factors ◽  
Heparan Sulfate ◽  
Cancer Progression ◽  
Core Protein ◽  
Heparan Sulfate Proteoglycans ◽  
Glycosylphosphatidylinositol Anchor ◽  
Multiple Ligands

Glypicans are a family of heparan sulfate proteoglycans that are attached to the cell membrane via a glycosylphosphatidylinositol anchor. Glypicans interact with multiple ligands, including morphogens, growth factors, chemokines, ligands, receptors, and components of the extracellular matrix through their heparan sulfate chains and core protein. Therefore, glypicans can function as coreceptors to regulate cell proliferation, cell motility, and morphogenesis. In addition, some glypicans are abnormally expressed in cancers, possibly involved in tumorigenesis, and have the potential to be cancer-specific biomarkers. Here, we provide a brief review focusing on the expression of glypicans in various cancers and their potential to be targets for cancer therapy.

scholarly journals Localization of anticoagulantly active heparan sulfate proteoglycans in vascular endothelium: antithrombin binding on cultured endothelial cells and perfused rat aorta.

1990 ◽  
Vol 111 (3) ◽  
pp. 1293-1304 ◽  
Author(s):  
A I de Agostini ◽  
S C Watkins ◽  
H S Slayter ◽  
H Youssoufian ◽  
R D Rosenberg
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Protease Inhibitor ◽  
Heparan Sulfate ◽  
Binding Sites ◽  
Rat Aorta ◽  
Linear Increase ◽  
Heparan Sulfate Proteoglycans ◽  
Vasa Vasorum

We have studied the interaction of 125I-antithrombin (125I-AT) with microvascular endothelial cells (RFPEC) to localize the cellular site of anticoagulantly active heparan sulfate proteoglycans (HSPG). The radiolabeled protease inhibitor bound specifically to the above HSPG with a Kd of approximately 50 nM. Confluent monolayer RFPEC cultures exhibited a linear increase in the amount of AT bound per cell for up to 16 d, whereas suspension RFPEC cultures possessed a constant number of protease inhibitor binding sites per cell for up to 5 d. These results suggest that monolayer RFPEC cultures secrete anticoagulantly active HSPG, which then accumulate in the extracellular matrix. This hypothesis was confirmed by quantitative light and EM level autoradiography which demonstrated that the AT binding sites are predominantly located in the extracellular matrix with only small quantities of protease inhibitor complexed to the cell surface. We have also pinpointed the in vivo position of anticoagulantly active HSPG within the blood vessel wall. Rat aortas were perfused, in situ, with 125I-AT, and bound labeled protease inhibitor was localized by light and EM autoradiography. The anticoagulantly active HSPG were concentrated immediately beneath the aortic and vasa vasorum endothelium with only a very small extent of labeling noted on the luminal surface of the endothelial cells. Based upon the above data, we propose a model whereby luminal and abluminal anticoagulantly active HSPG regulate coagulation mechanism activity.

Emerging Roles of Heparan Sulfate Proteoglycans in Viral Pathogenesis

2021 ◽  
Vol 47 (03) ◽  
pp. 283-294 ◽  
Author(s):  
Raghuram Koganti ◽  
Abdullah Memon ◽  
Deepak Shukla
Keyword(s):  
Extracellular Matrix ◽  
Human Immunodeficiency Virus ◽  
Heparan Sulfate ◽  
Viral Entry ◽  
Structural Integrity ◽  
Viral Pathogenesis ◽  
Heparan Sulfate Proteoglycans ◽  
Cytokines And Chemokines ◽  
Immunodeficiency Virus ◽  
Mammalian Tissues

AbstractHeparan sulfate is a glycosaminoglycan present in nearly all mammalian tissues. Heparan sulfate moieties are attached to the cell surface via heparan sulfate proteoglycans (HSPGs) which are composed of a protein core bound to multiple heparan sulfate chains. HSPGs contribute to the structural integrity of the extracellular matrix and participate in cell signaling by releasing bound cytokines and chemokines once cleaved by an enzyme, heparanase. HSPGs are often exploited by viruses during infection, particularly during attachment and egress. Loss or inhibition of HSPGs initially during infection can yield significant decreases in viral entry and infectivity. In this review, we provide an overview of HSPGs in the lifecycle of multiple viruses, including herpesviruses, human immunodeficiency virus, dengue virus, human papillomavirus, and coronaviruses.

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