The Putative Tumor Suppressors EXT1 and EXT2 Are Glycosyltransferases Required for the Biosynthesis of Heparan Sulfate

Lind, Thomas; Tufaro, Frank; McCormick, Craig; Lindahl, Ulf; Lidholt, Kerstin

doi:10.1074/jbc.273.41.26265

Cited by 405 publications

(319 citation statements)

References 35 publications

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“…The biosynthesis of HS is performed by a complex pathway involving chain elongation and multiple modification steps ( Figure 3). Synthesis is initiated with addition of a linkage region domain (LRD) to a specific Ser residues on the protein followed by elongation steps to generate the unsulfated and unepimerized polysaccharide backbone consisting of GlcUA-GlcNAc disaccharide repeats (26,27).…”

Section: Biosynthesis Of Anticoagulant Hs Biosynthetic Pathwaymentioning

confidence: 99%

Anticoagulant heparan sulfate: structural specificity and biosynthesis

Liu

Pedersen

2007

Appl Microbiol Biotechnol

123

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SummaryHeparan sulfate (HS) is present on the surface of endothelial and surrounding tissues in large quantities. It plays important roles in regulating numerous functions of the blood vessel wall, including blood coagulation, inflammation response and cell differentiation. HS is a highly sulfated polysaccharide containing glucosamine and glucuronic/iduronic acid repeating disaccharide units. The unique sulfated saccharide sequences of HS determine its specific functions. Heparin, an analogue of heparan sulfate, is the most commonly used anticoagulant drug. Because of its wide range of biological functions, HS has become an interesting molecule to biochemists, medicinal chemists and developmental biologists. Here, we summarize recent progress towards understanding the interaction between heparan sulfate and blood coagulating factors, the biosynthesis of anticoagulant heparan sulfate and the mechanism of action of heparan sulfate biosynthetic enzymes. Further, knowledge of the biosynthesis of HS facilitates the development of novel enzymatic approaches to synthesize HS from bacterial capsular polysaccharides and to produce polysaccharide end products with high specificity for the biological target. These advancements provide the foundation for the development of polysaccharide-based therapeutic agents.

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Section: Biosynthesis Of Anticoagulant Hs Biosynthetic Pathwaymentioning

confidence: 99%

Anticoagulant heparan sulfate: structural specificity and biosynthesis

Liu

Pedersen

2007

Appl Microbiol Biotechnol

123

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“…In Drosophila embryos, HSPG biosynthesis is abrogated in the absence of Ttv activity (The et al 1999), and in vertebrates, the EXT proteins function similarly in the HSPG biosynthesis pathway (Lind et al 1998;McCormick et al 1998;Toyoda et al 2000a, b). We asked whether the hEXT1 transgene is able to effectively restore HSPG biosynthesis in homozygous ttv mutant embryos.…”

Section: Fig 2 Hspg Biosynthesis In Ttv Mutant Embryos Is Rescued Bymentioning

confidence: 99%

“…The EXT genes encode for type II transmembrane glycoproteins that localize predominantly to the endoplasmic reticulum (ER) and golgi. They form a heterooligomeric complex in the golgi apparatus (Kobayashi et al 2000;McCormick et al 2000) and are involved in the synthesis of heparan sulfate glycosaminoglycans (HSGAGs; Lind et al 1998;McCormick et al 1998McCormick et al , 2000Toyoda et al 2000b;Wei et al 2000). Heparan sulfate proteoglycans (HSPGs) consist of a glycosylated protein core, which can either be a transmembrane, glycosylphosphatidyl-inositol (GPI)-linked, or secreted protein, and they are abundant on the cell surface and extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

et al. 2007

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Heparan sulfate proteoglycans play a vital role in signaling of various growth factors in both Drosophila and vertebrates. In Drosophila, mutations in the tout velu (ttv) gene, a homolog of the mammalian EXT1 tumor suppressor gene, leads to abrogation of glycosaminoglycan (GAG) biosynthesis. This impairs distribution and signaling activities of various morphogens such as Hedgehog (Hh), Wingless (Wg), and Decapentaplegic (Dpp). Mutations in members of the exostosin (EXT) gene family lead to hereditary multiple exostosis in humans leading to bone outgrowths and tumors. In this study, we provide genetic and biochemical evidence that the human EXT1 (hEXT1) gene is conserved through species and can functionally complement the ttv mutation in Drosophila. The hEXT1 gene was able to rescue a ttv null mutant to adulthood and restore GAG biosynthesis.

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“…The first insights into a role of HSPGs in hedgehog function came from studies of a Drosophila phenotype caused by mutations in toutvelu, a gene that turned out to be homologous to vertebrate EXT-1 and EXT-2 genes involved in heparan sulfate synthesis (Bellaiche et al, 1998;Lind et al, 1998). As pointed out above, HS-PG roles in hedgehog function have been confirmed and extended by several subsequent studies.…”

Section: Discussionmentioning

confidence: 94%

Indian hedgehog and syndecans‐3 coregulate chondrocyte proliferation and function during chick limb skeletogenesis

Shimo

Gentili

Iwamoto

et al. 2004

Developmental Dynamics

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Hedgehog proteins exert critical roles in embryogenesis and require heparan sulfate proteoglycans (HS-PGs) for action. Indian hedgehog (Ihh) is produced by prehypertrophic chondrocytes in developing long bones and regulates chondrocyte proliferation and other events, but it is not known whether it requires HS-PGs for function. Because the HS-PG syndecan-3 is preferentially expressed by proliferating chondrocytes, we tested whether it mediates Ihh action. Primary chick chondrocyte cultures were treated with recombinant Ihh (rIhh-N) in absence or presence of heparinase I or syndecan-3 neutralizing antibodies. While rIhh-N stimulated proliferation in control cultures, it failed to do so in heparinase-or antibody-treated cultures. In reciprocal gain-of-function studies, chondrocytes were made to overexpress syndecan-3 by an RCAS viral vector. Cells became more responsive to rIhh-N, but even this response was counteracted by heparinase or antibody treatment. To complement the in vitro data, RCAS viral particles were microinjected in day 4 -5 chick wing buds and effects of syndecan-3 misexpression were monitored over time. Syndecan-3 misexpression led to widespread chondrocyte proliferation and, interestingly, broader expression and distribution of Ihh. In addition, the syndecan-3 misexpressing skeletal elements were short, remained cartilaginous, lacked osteogenesis, and exhibited a markedly reduced expression of collagen X and osteopontin, products characteristic of hypertrophic chondrocytes and bone cells. The data are the first to indicate that Ihh action in chondrocyte proliferation involves syndecan-3 and to identify a specific member of the syndecan family as mediator of hedgehog function. Developmental Dynamics 229:607-617, 2004.

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The Putative Tumor Suppressors EXT1 and EXT2 Are Glycosyltransferases Required for the Biosynthesis of Heparan Sulfate

Cited by 405 publications

References 35 publications

Anticoagulant heparan sulfate: structural specificity and biosynthesis

Anticoagulant heparan sulfate: structural specificity and biosynthesis

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

Indian hedgehog and syndecans‐3 coregulate chondrocyte proliferation and function during chick limb skeletogenesis

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