Multimeric heparan sulfate modulates FGF signaling in zebrafish development
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Heparan sulfate proteoglycans (HSPGs) play crucial roles in a number of signaling pathways during development through binding to various secreted molecules such as FGF, WNT, SHH and BMP. Most of the studies examined the interactions between these secreted proteins with monomeric heparin sequences. However, almost all endogenous proteoglycans (PGs) possess two or more glycosaminoglycan (GAG) chains. This study is the first attempt to stimulate the expressions of endogenous PG mimetics with two or more HS chains connected covalently in an animal model to investigate the roles of these molecules in various signaling events. A library of monomeric and multimeric xylosides, which prime GAG chains, was examined in zebrafish embryos. We found that only clustered HS chains primed by multimeric xylosides hyperactivated the FGF/FGFR mediated signaling pathways leading to elongation of zebrafish embryos. Based on our findings, we propose that multimeric HS is required for the formation of biologically relevant HS/FGF/FGFR ternary complexes, leading to receptor dimerization in vivo and subsequent cell signaling events.Keywords:
Cell Signaling
In conclusion, retinoids modulate phenotypic changes such as morphology, adhesion, and growth rate. These changes also result in specific alterations of glycosaminoglycans. We have observed increases in the degree of sulfation in fibroblast matrix heparan sulfate and, a change in the ratio of sulfamido to ester sulfate in matrix heparan sulfate in 407 cell surface. Matrix glycosaminoglycans have been functionally implicated in cellular interactions, and have a specific role in adhesion and growth rates. Our results are consistent with the proposed role for heparan sulfate. It is possible that some of the modulation in cellular behavior resulting from retinoid treatment may be mediated by cell surface and cellular changes in heparan sulfate and other glycosaminoglycans.
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Fibroblast growth factors FGF-1 and FGF-2 mediate their biological effects via heparan sulfate-dependent interactions with cell surface FGF receptors. While the specific heparan sulfate domain binding to FGF-2 has been elucidated in some detail, limited information has been available concerning heparan sulfate structures involved in the recognition of FGF-1. In the current study we present evidence that the minimal FGF-1 binding heparan sulfate sequence comprises 5–7 monosaccharide units and contains a critical trisulfated IdoA(2-OSO3)-GlcNSO3(6-OSO3) disaccharide unit. N-Sulfated heparan sulfate decasaccharides depleted of FGF-1 binding domains showed dose-dependent and saturable binding to FGF-2. These data indicate that the FGF-1 binding domain is distinct from the minimal FGF-2 binding site, previously shown to contain an IdoA(2-OSO3) residue but no 6-O-sulfate groups. We further show that the FGF-1 binding heparan sulfate domain is expressed in human aorta heparan sulfate in an age-related manner in contrast to the constitutively expressed FGF-2 binding domain. Reduction of heparan sulfate O-sulfation by chlorate treatment of cells selectively impedes binding to FGF-1. The present data implicate the 6-O-sulfation of IdoA(2-OSO3)-GlcNSO3 units in cellular heparan sulfate in the control of the biological activity of FGF-1.
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"Fibroblast-like" cells from the intimal layer of bovine aorta were grown in culture. The formation, composition, molecular weight and turnover rate of different pools of glycosaminoglycans were investigated in cultures incubated in the presence [35S]sulfate or [14C]glucosamine. The newly synthesized glycosaminoglycans are distributed into an extracellular pool (37 - 58%), a cell-membrane associated or pericellular pool (23 - 33%), and an intracellular pool (19 - 30%), each pool exhibiting a characteristic distribution pattern of chondroitin sulfate, dermatan sulfate, heparan sulfate and hyaluronate. The distribution pattern of the extracellular glycosaminoglycans resembles closely that found in bovine aorta. A small subfraction of the pericellular pool - tentatively named "undercellular" pool--has been characterized by its high heparan sulfate content. The intracellular and pericellular [35S]glycosaminoglycan pools reach a constant radioactivity after 8-12 h and 24 h, respectively, whereas the extracellular [35S]glycosaminoglycans are secreted into the medium at a linear rate over a period of at least 6 days. The intracellular glycosaminoglycans are mainly in the process of degradation, as indicated by their low molecular weight and by their half-life of 7 h, but intracellular dermatan sulfate is degraded more rapidly (half-life 4-5 h) than intracellular chondroitin sulfate and heparan sulfate (half-life 7-8 h). Glycosaminoglycans leave the pericellular pool with a half-life of 12-14 h by 2 different routes: about 60% disappear as macromolecules into the culture medium, and the remainder is pinocytosed and degraded to a large extent. Extracellular and at least a part of the pericellular glycosaminoglycans are proteoglycans. Even under dissociative conditions (4M guanidinium chloride) their hydrodynamic volume is sufficient for partial exclusion from Sepharose 4B gel. The existence of topographically distinct glycosaminoglycan pools with varying metabolic characteristics and differing accessibility for degradation requiresa reconsideration and a more reserved interpretation of results concerning the turnover rates of glycosaminoglycans as determined in arterial tissue.
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Protamine sulfate
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The characterization of intracellularly stored glycosaminoglycans from organs of a patient suffering from mucopolysaccharidosis III A (Sanfilippo A disease) is described. Both heparan sulfate and galactosamine-containing glycosaminoglycans (chondroitin sulfate, dermatan sulfate) are accumulated in the liver, whereas in the other organs (spleen, kidney, heart, cerebrum, cerebellum) heparan sulfate is almost the only glycosaminoglycan stored. It is shown by [3H]NaBH4 reduction and subsequent identification of the 3H-labelled sugar alcohols that heparan sulfate is degraded in all organs by at least two endoglycosidases, an endoglucuronidase and an endoglucosaminidase, to fragments of low molecular weight (Mr approximately 2 000-6 600).
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The influence of a glycosaminoglycan polysulfate (GAGPS) on the glycosaminoglycan (GAG) metabolism was investigated in relation to in vitro ageing of cultured human lung fibroblasts (Flow 2002). The incorporation of 35S-sulfate was determined following proteolytic digestion and specific degradation methods for the individual GAGs. In untreated cultures the pericellular matrix and medium showed a decrease of chondroitin sulfate (CS) 35S-radioactivity of the higher passage numbers, while the pericellular heparan sulfate (HS) showed increasing values. In GAGPS-treated cultures the decrease of 35S-sulfate incorporation into CS and dermatan sulfate of the cells and medium as well as into the pericellular CS was negatively correlated to the passage numbers, since GAGPS preferentially increased the radioactivity in cultures of low passage numbers. The HS values, however, were changed in the same direction as observed in untreated controls. Thus, age-related changes in the GAG metabolism become visible when exogenous GAGPS is used as a stimulus.
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The incorporation of [35S]sulfate into glycosaminoglycans was studied in cultures of normal and diabetic skin fibroblasts. Heparan sulfate was determined by column chromatography after enzymatic degradation of chondroitin sulfates and dermatan sulfate by chondroitinase ABE. Cultured skin fibroblasts from both insulin-dependent and noninsulin-dependent diabetics were found to have increased proportions of heparan sulfate in the media relative to the other sulfated glycosaminoglycans.
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Fibroblast growth factors (FGFs) comprise a large family of developmental and physiological signaling molecules. All FGFs have a high affinity for the glycosaminoglycan heparin and for cell surface heparan sulfate proteoglycans. A large body of biochemical and cellular evidence points to a direct role for heparin/heparan sulfate in the formation of an active FGF/FGF receptor signaling complex. However, until recently there has been no direct demonstration that heparan is required for the biological activity of FGF in a developmental system in vivo. A recent paper by Lin et al.(1) has broken through this barrier to demonstrate that heparan sulfate is essential for FGF function during Drosophila development. The establishment of a role for heparan sulfate in FGFR activation in vivo suggests that tissue-specific differences in the structure of heparan may modulate the activity of FGF. BioEssays 22:108–112, 2000. ©2000 John Wiley & Sons, Inc.
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