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Information on EC 2.4.1.224 - glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase and Organism(s) Mus musculus and UniProt Accession P97464
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2.4.1.224 glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferaseIUBMB Comments
Involved in the biosynthesis of heparin and heparan sulfate. Some forms of the enzyme from human (particularly the enzyme complex encoded by the EXT1 and EXT2 genes) act as bifunctional glycosyltransferases, which also have the 4-beta-glucuronosyltransferase (EC 2.4.1.225, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase) activity required for the synthesis of the heparan sulfate disaccharide repeats. Other human forms of this enzyme (e.g. the product of the EXTL1 gene) have only the 4-alpha-N-acetylglucosaminyltransferase activity. In Caenorhabditis elegans, the product of the rib-2 gene displays the activities of this enzyme as well as EC 2.4.1.223, glucuronosyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase.
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Word Map
- 2.4.1.224
- proteoglycans
- exostoses
- osteochondroma
- glycosaminoglycans
- glycosyltransferase
-
hedgehog
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hspgs
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chondrosarcoma
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cartilaginous
- syndecan-1
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glypicans
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cartilage-capped
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wingless
- perlecan
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metaphyses
-
decapentaplegic
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co-polymerase
- medicine
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria
Reaction Schemes
Synonyms
exostosin-1, exostosin-2, tout-velu, sister of tout-velu, exostosin1, heparan sulfate polymerase, exostosin2, sister of tout velu, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
alpha-N-acetylglucosaminyltransferase II
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-
-
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glucuronyl-N-acetylglucosaminoproteoglycan 4-alpha-N-acetylglucosaminyltransferase
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-
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heparan sulfate polymerase
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N-acetyl-D-glucosaminyl-(N-acetyl-D-glucosamine) transferase
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UDP-GlcNAc:oligosaccharide beta-N-acetylglucosaminyltransferase
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
transfer of alpha-N-acetylglucosamine
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-
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SYSTEMATIC NAME
IUBMB Comments
UDP-N-acetyl-D-glucosamine:beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase
Involved in the biosynthesis of heparin and heparan sulfate. Some forms of the enzyme from human (particularly the enzyme complex encoded by the EXT1 and EXT2 genes) act as bifunctional glycosyltransferases, which also have the 4-beta-glucuronosyltransferase (EC 2.4.1.225, N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase) activity required for the synthesis of the heparan sulfate disaccharide repeats. Other human forms of this enzyme (e.g. the product of the EXTL1 gene) have only the 4-alpha-N-acetylglucosaminyltransferase activity. In Caenorhabditis elegans, the product of the rib-2 gene displays the activities of this enzyme as well as EC 2.4.1.223, glucuronosyl-galactosyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase.
CAS REGISTRY NUMBER
COMMENTARY
145539-84-0
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336193-98-7
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
UDP-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
UDP-N-acetyl-D-glucosamine + [D-glucuronic acid-N-acetyl-glucosamine]14 -D-glucuronic acid-2,5-anhydro-D-mannose
?
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + [D-glucuronic acid-N-acetyl-glucosamine]4 -D-glucuronic acid-2,5-anhydro-D-mannose
?
-
-
-
-
?
UDP-N-acetyl-D-glucosamine + [D-glucuronosyl-beta-(1->4)-N-acetyl-D-glucoseamin-alpha-(1->4)]n-D-glucuronosyl-2,5-anhydro-D-mannose
UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-[D-glucuronosyl-beta-(1->4)-N-acetyl-D-glucoseaminyl-alpha-(1->4)]n-D-glucuronosyl-2,5-anhydro-D-mannose
UDP-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
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-
-
-
?
UDP-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
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elongation of growing chains of heparin and heparan sulfate, tumor suppressor
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-
?
UDP-N-acetyl-D-glucosamine + [D-glucuronosyl-beta-(1->4)-N-acetyl-D-glucoseamin-alpha-(1->4)]n-D-glucuronosyl-2,5-anhydro-D-mannose
UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-[D-glucuronosyl-beta-(1->4)-N-acetyl-D-glucoseaminyl-alpha-(1->4)]n-D-glucuronosyl-2,5-anhydro-D-mannose
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different activities observed for acetylated and sulfated acceptors
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-
?
UDP-N-acetyl-D-glucosamine + [D-glucuronosyl-beta-(1->4)-N-acetyl-D-glucoseamin-alpha-(1->4)]n-D-glucuronosyl-2,5-anhydro-D-mannose
UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-[D-glucuronosyl-beta-(1->4)-N-acetyl-D-glucoseaminyl-alpha-(1->4)]n-D-glucuronosyl-2,5-anhydro-D-mannose
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substrate is produced by E. coli K5, acceptor ability increases with increasing chain length
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?
additional information
?
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EXT1 and EXT2 proteins also acts as beta(1,4)-glucuronyltransferase (EC 2.4.1.225)
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?
additional information
?
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EXT1 and EXT2 proteins also acts as beta(1,4)-glucuronyltransferase (EC 2.4.1.225)
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-
?
additional information
?
-
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EXT1 and EXT2 proteins also acts as beta(1,4)-glucuronyltransferase (EC 2.4.1.225)
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?
additional information
?
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the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
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-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
UDP-N-acetyl-D-glucosamine + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
UDP + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-proteoglycan
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elongation of growing chains of heparin and heparan sulfate, tumor suppressor
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-
?
additional information
?
-
-
the Ext1/Ext2 complex possesses higher glycosyltransferase activity than Ext1 or Ext2 alone
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.006
[D-glucuronic acid-N-acetyl-glucosamine]14 -D-glucuronic acid-2,5-anhydro-D-mannose
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0.06
[D-glucuronic acid-N-acetyl-glucosamine]4 -D-glucuronic acid-2,5-anhydro-D-mannose
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
the mRNA expression of EXT2, one of the crucial enzymes for heparan sulfate-glycosaminoglycan synthesis, is markedly up-regulated in injured hypoglossal motor neurons after axotomy
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FBJ, highly metastatic mouse osteosarcoma FBJ-LL cells and the poorly metastatic FBJ-S1 cells are produced from a FBJ virus-induced osteosarcoma
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
Ext1 and Ext2 are type II transmembrane glycoproteins
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
Exostosin glycosyltransferases exclusively catalyze heparan sulfate polymerization. Heparan sulfate/heparin, chondroitin sulfate, dermatan sulfate, and keratan sulfate form glycosaminoglycans, long linear polysaccharide chains consisting of repeat disaccharide units. Glycosaminoglycans are the major components of the extracellular matrix and play critical roles in regulating transport and signaling of numerous growth factors during embryonic development
physiological function
malfunction
physiological function
malfunction
deletion of Ext1 in the mesoderm induces a cardiac phenotype similar to that of a mutant with conditional deletion of UDP-glucose dehydrogenase, a key enzyme responsible for synthesis of all glycosaminoglycans. The outflow tract defect in conditional Ext1 knockout (Ext1f/f:Mesp1Cre) mice is attributable to the reduced contribution of second heart field and neural crest cells. Ext1 deletion leads to downregulation of FGF signaling in the pharyngeal mesoderm. Exogenous FGF8 ameliorates the defects in the outflow tract and pharyngeal explants. Phenotype, detailed overview
malfunction
ectopic cartilage forms in Ext1-deficient mouse embryo long bones, phenotype overview. perichondrium phenotype and border function regulation is deregulated in hereditary multiple exostoses. Ext1 deficiency stimulates cartilage formation
malfunction
effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo, phenotype, overview
physiological function
Ext1 is a glycosyltransferase responsible for heparan sulfate synthesis. Function of Ext1 in heart development, overview. Ext1 expression in second heart field and neural crest cells is required for outflow tract remodeling. Ext1 is crucial for outflow tract formation in distinct progenitor cells, and heparan sulfate modulates FGF signaling during early heart development. Proper expression of Ext1 is required for cardiogenesis, heparan sulfate is required for heart development
physiological function
heparan sulfate elongation genes EXT1 and EXT2 are involved in heparan sulfate elongation and in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability
physiological function
perichondrium phenotype and border function are deranged by Ext1 and heparan sulfate in developing long bones, and in ectopic cartilage formation
malfunction
-
EXT1 influences fibroblast matrix interactions. Essential role of EXT1 in providing specific binding sites for growth factors and extracellular matrix proteins. Phosphorylation of ERK1/2 in response to FGF2 stimulation is markedly decreased in the Ext1 mutant fibroblasts, whereas neither PDGF-BB nor FGF10 signaling is significantly affected. Ext1 mutants display reduced ability to attach to collagen I and to contract collagen lattices. Reintroduction of Ext1 in Ext1 mutant fibroblasts rescues heparan sulfate chain length, FGF2 signaling, and the ability of the fibroblasts to contract collagen
malfunction
-
a reduction in either Ext1 or Ext2 can cause a reduction in heparan sulfate biosynthesis, overview. Suppression of Ext1 by siRNA in FBJ-S1 cells results in the decreased expression of heparan sulfate and enhanced motility
malfunction
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conditional Ext1 mutant mice display severe limb skeletal defects, including shortened and malformed limb bones, oligodactyly, and fusion of joints. the segregation of the pSmad1/5/8-expressing chondrocytes and fibronectin-expressing perichondrium-like cells surrounding chondrocyte nodules is disrupted in mutant micromass cultures, Ext2-mutant phenotypes, detailed overview
malfunction
effect of heterozygous mutations in heparan sulfate elongation genes EXT1 and EXT2 on endothelial function in vitro as well as in vivo, phenotype, overview
physiological function
-
Ext1 and Ext2 are tumor suppressors. In the biosynthesis of heparan sulfate, after the attachment of a GlcNAc residue to GlcA-Gal-Gal-Xyl, Ext1 and Ext2 catalyze the subsequent elongation of glycosaminoglycans by alternately adding GlcA and GlcNAc to the end of the growing chain. Involvement of Ext1 and heparanase in migration of FBJ osteosarcoma cells, overview
physiological function
-
Ext1 encodes an essential glycosyltransferase for heparan sulfate synthesis, heparan sulfate is essential for patterning of limb skeletal elements
physiological function
heparan sulfate elongation genes EXT1 and EXT2 are involved in heparan sulfate elongation and in maintaining endothelial homeostasis, presumably via increased nitric oxide bioavailability
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). EXT1_MOUSE
746
1
86308
Swiss-Prot
Secretory Pathway (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
glycoprotein
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N-linked glycosylation, Endo H treatment does not effect 80000 Da species but reduces size of 90000 Da species that is found mainly when both proteins are coexpressed
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
generation of Ext1+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext1+/- mice compared to wild-type littermates
additional information
generation of Ext1+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext1+/- mice compared to wild-type littermates
additional information
-
d620EXT1myc deletion mutant without 620 C-terminal amino acids, no enzymatic activity, ER localization
additional information
-
generation of conditional Ext1 mutant mice by crossing the Ext1flox allele and the Prx1-Cre transgene
additional information
generation of Ext2+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext2+/- mice compared to wild-type littermates
additional information
generation of Ext2+/- mice, endothelial glycocalyx and maximal arteriolar dilatation are significantly altered in Ext2+/- mice compared to wild-type littermates
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene EXT1, creation of loxP-modified Ext1 allele and establishment of the Ext1 floxed mouse line (Ext1flox/flox), expression of the enzyme in Gdf-5-Cre transgenic mice, semiquantitative real-time PCR enzyme expression analysis
completion of mutant sog9 with HeLa cDNA, restores susceptibility to HSV-1 infection
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expression of full length and truncated form in Pichia pastoris and COS-1 cells, dramatic increase of activity when full length EXT1 and EXT2 are coexpressed, no increase of activity when mixing extract containing EXT1 and EXT2 protein
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EXT1 and EXT2 from wild type CHO used to complement deficiency mutant CHO-K1, EXT2 failed to complement functional deficiency while it was fully corrected by EXT1
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full-length Ext1 cDNA cloned into the pBudCE4.1 vector and transfected into Ext1Gt/Gt fibroblasts
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Senay, C.; Lind, T.; Muguruma, K.; Tone, Y.; Kitagawa, H.; Sugahara, K.; Lidholt, K.; Lindahl, U.; Kusche-Gullberg, M.
The EXT1/EXT2 tumor suppressors: catalytic activities and role in heparan sulfate biosynthesis
EMBO Rep.
1
282-286
2000
Bos taurus, Mus musculus, no activity in yeast
Lind, T.; Tufaro, F.; McCormick, C.; Lindahl, U.; Lidholt, K.
The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate
J. Biol. Chem.
273
26265-26268
1998
Mus musculus, Bos taurus (O77783)
Lidholt, K.; Lindahl, U.
Biosynthesis of heparin. The D-glucuronosyl- and N-acetyl-D-glucosaminyltransferase reactions and their relation to polymer modification
Biochem. J.
287
21-29
1992
Bos taurus, Mus musculus
-
Lidholt, K.; Fjelstad, M.; Jann, K.; Lindahl, U.
Biosynthesis of heparin. XXV. Substrate specificities of glucosyltransferases involved in formation of heparin precursor and E. coli K5 capsular polysaccharides
Carbohydr. Res.
255
87-101
1994
Escherichia coli, Escherichia coli O18:K5, Mus musculus
Wei, G.; Bai, X.; Gabb, M.M.G.; Bame, K.J.; Koshy, T.I.; Spear, P.G.; Esko, J.D.
Location of the glucuronosyltransferase domain in the heparan sulfate copolymerase EXT1 by analysis of Chinese hamster ovary cell mutants
J. Biol. Chem.
275
27733-27740
2000
Cricetinae, Homo sapiens, Mus musculus
McCormic, C.; Leduc, Y.; Martindale, D.; Mattison, K.; Esford, L.E.; Dyer, A.P.; Tufaro, F.
The putative tumor suppressor EXT 1 alters the expression of cell surface heparan sulfate
Nat. Genet.
19
158-161
1998
Cricetinae, Mus musculus
Murakami, K.; Namikawa, K.; Shimizu, T.; Shirasawa, T.; Yoshida, S.; Kiyama, H.
Nerve injury induces the expression of EXT2, a glycosyltransferase required for heparan sulfate synthesis
Neuroscience
141
1961-1969
2006
Mus musculus
Osterholm, C.; Barczyk, M.M.; Busse, M.; Gronning, M.; Reed, R.K.; Kusche-Gullberg, M.
Mutation in the heparan sulfate biosynthesis enzyme EXT1 influences growth factor signaling and fibroblast interactions with the extracellular matrix
J. Biol. Chem.
284
34935-34943
2009
Mus musculus
Matsumoto, Y.; Matsumoto, K.; Irie, F.; Fukushi, J.; Stallcup, W.B.; Yamaguchi, Y.
Conditional ablation of the heparan sulfate-synthesizing enzyme Ext1 leads to dysregulation of bone morphogenic protein signaling and severe skeletal defects
J. Biol. Chem.
285
19227-19234
2010
Mus musculus, Mus musculus C57BL/6
Wang, Y.; Yang, X.; Yamagata, S.; Yamagata, T.; Sato, T.
Involvement of Ext1 and heparanase in migration of mouse FBJ osteosarcoma cells
Mol. Cell. Biochem.
373
63-72
2013
Mus musculus, Mus musculus BALB/c
Huegel, J.; Mundy, C.; Sgariglia, F.; Nygren, P.; Billings, P.C.; Yamaguchi, Y.; Koyama, E.; Pacifici, M.
Perichondrium phenotype and border function are regulated by Ext1 and heparan sulfate in developing long bones: a mechanism likely deranged in hereditary multiple exostoses
Dev. Biol.
377
100-112
2013
Mus musculus (P97464)
Mooij, H.L.; Cabrales, P.; Bernelot Moens, S.J.; Xu, D.; Udayappan, S.D.; Tsai, A.G.; van der Sande, M.A.; de Groot, E.; Intaglietta, M.; Kastelein, J.J.; Dallinga-Thie, G.M.; Esko, J.D.; Stroes, E.S.; Nieuwdorp, M.
Loss of function in heparan sulfate elongation genes EXT1 and EXT 2 results in improved nitric oxide bioavailability and endothelial function
J. Am. Heart Assoc.
3
e001274
2014
Homo sapiens (Q16394), Homo sapiens (Q93063), Mus musculus (P70428), Mus musculus (P97464)
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