Reviewed, UniProtKB/Swiss-Prot Q93063 (EXT2_HUMAN)

Names and origin

Protein names

Recommended name:
    Exostosin-2
    EC=2.4.1.224
    EC=2.4.1.225
Alternative name(s):
    Glucuronosyl-N-acetylglucosaminyl-proteoglycan/N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase
    Putative tumor suppressor protein EXT2
    Multiple exostoses protein 2

Gene names

Name:

EXT2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	718 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Glycosyltransferase required for the biosynthesis of heparan-sulfate. The EXT1/EXT2 complex possesses substantially higher glycosyltransferase activity than EXT1 or EXT2 alone. Appears to be a tumor suppressor.
Catalytic activity	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-alpha-D-glucuronate + N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan = UDP + beta-D-glucuronosyl-(1->4)-N-acetyl-alpha-D-glucosaminyl-(1->4)-beta-D-glucuronosyl-proteoglycan.
Pathway	Protein modification; protein glycosylation.
Subunit structure	Forms a homo/hetero-oligomeric complex with EXT1. Interacts with GALNT5. Ref.6 Ref.7
Subcellular location	Endoplasmic reticulum membrane; Single-pass type II membrane protein. Golgi apparatus membrane; Single-pass type II membrane protein. Note= The EXT1/EXT2 complex is localized in the Golgi apparatus. Ref.6
Tissue specificity	Ubiquitous.
Involvement in disease	Defects in EXT2 are a cause of hereditary multiple exostoses type 2 (EXT2) [MIM:133701]. EXT is a genetically heterogeneous bone disorder caused by genes segregating on human chromosomes 8, 11, and 19 and designated EXT1, EXT2 and EXT3 respectively. EXT is a dominantly inherited skeletal disorder primarily affecting endochondral bone during growth. The disease is characterized by formation of numerous cartilage-capped, benign bone tumors (osteocartilaginous exostoses or osteochondromas) that are often accompanied by skeletal deformities and short stature. In a small percentage of cases exostoses have exhibited malignant transformation resulting in an osteosarcoma or chondrosarcoma. Osteochondromas development can also occur as a sporadic event. Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Defects in EXT2 are the cause of multiple exostoses observed in Potocki-Shaffer syndrome [MIM:601224]. It is a contiguous gene syndrome due to proximal deletion of chromosome 11p11.2, including EXT2 and ALX4.
Sequence similarities	Belongs to the glycosyltransferase 47 family.

Ontologies

Keywords
Biological process	Cell cycle
Cellular component	Endoplasmic reticulum Golgi apparatus Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation Hereditary multiple exostoses
Domain	Signal-anchor Transmembrane
Molecular function	Anti-oncogene Glycosyltransferase Transferase
PTM	Glycoprotein
Gene Ontology (GO)
Biological process	glycosaminoglycan biosynthetic process Inferred from direct assay. Source: UniProtKB heparan sulfate proteoglycan biosynthetic process, polysaccharide chain biosynthetic process Inferred from mutant phenotype. Source: UniProtKB negative regulation of cell cycle Inferred from electronic annotation. Source: UniProtKB-KW ossification Ref.9 Inferred from mutant phenotype. Source: UniProtKB signal transduction Traceable author statement. Source: ProtInc
Cellular component	Golgi membrane Inferred from electronic annotation. Source: UniProtKB-SubCell endoplasmic reticulum membrane Traceable author statement. Source: ProtInc integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity Inferred from electronic annotation. Source: EC glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity Inferred from electronic annotation. Source: EC heparan sulfate N-acetylglucosaminyltransferase activity Non-traceable author statement. Source: UniProtKB protein heterodimerization activity Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
CNTF	P26441	1	EBI-1047761,EBI-1050897
FABP4	P15090	1	EBI-1047761,EBI-715333
HNF4A	P41235	1	EBI-1047761,EBI-1049011
HYOU1	Q9Y4L1	1	EBI-1047761,EBI-1054186
RPS29	P62273	1	EBI-1047761,EBI-1054121
SNCG	O76070	1	EBI-1047761,EBI-1053810
STK16	O75716	1	EBI-1047761,EBI-1046308
TCEB1	Q15369	1	EBI-1047761,EBI-301231

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q93063-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q93063-2)

The sequence of this isoform differs from the canonical sequence as follows:
     392-411: ARWFWEAYFQSIKAIALATL → LFMEPVRRENWSAANHQMNSLIWPREQWDS

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 718	718	Exostosin-2		PRO_0000149651
Regions
	Topological domain	1 – 25	25	Cytoplasmic Potential
	Transmembrane	26 – 46	21	Signal-anchor for type II membrane protein Potential
	Topological domain	47 – 718	672	Lumenal Potential
Amino acid modifications
	Glycosylation	288	1	N-linked (GlcNAc...) Potential
	Glycosylation	637	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	392 – 411	20	ARWFW…ALATL → LFMEPVRRENWSAANHQMNS LIWPREQWDS in isoform 2.		VSP_001798
	Natural variant	42	1	M → V: dbSNP rs4755779.		VAR_033921
	Natural variant	85	1	C → R in EXT2. Ref.11		VAR_012823
	Natural variant	152	1	L → R in EXT2. Ref.10		VAR_012824
	Natural variant	179	1	R → S in EXT2. Ref.16		VAR_012825
	Natural variant	202	1	A → V in EXT2. Ref.13		VAR_012826
	Natural variant	223	1	R → P in EXT2. Ref.12		VAR_012827
	Natural variant	227	1	D → N in EXT2; can still form an oligomeric complex. Ref.9 Ref.14 Ref.16		VAR_002378
	Natural variant	380	1	I → T in EXT2. Ref.15		VAR_012828
	Natural variant	576	1	E → K in osteochondroma. Ref.15		VAR_012829
Experimental info
	Sequence conflict	568	1	G → D in AAB62718. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 1, 1997. Version 1. Checksum: 9048CD3A5B63C5CB	FASTA	718	82,255
	10 20 30 40 50 60 MCASVKYNIR GPALIPRMKT KHRIYYITLF SIVLLGLIAT GMFQFWPHSI ESSNDWNVEK 70 80 90 100 110 120 RSIRDVPVVR LPADSPIPER GDLSCRMHTC FDVYRCGFNP KNKIKVYIYA LKKYVDDFGV 130 140 150 160 170 180 SVSNTISREY NELLMAISDS DYYTDDINRA CLFVPSIDVL NQNTLRIKET AQAMAQLSRW 190 200 210 220 230 240 DRGTNHLLFN MLPGGPPDYN TALDVPRDRA LLAGGGFSTW TYRQGYDVSI PVYSPLSAEV 250 260 270 280 290 300 DLPEKGPGPR QYFLLSSQVG LHPEYREDLE ALQVKHGESV LVLDKCTNLS EGVLSVRKRC 310 320 330 340 350 360 HKHQVFDYPQ VLQEATFCVV LRGARLGQAV LSDVLQAGCV PVVIADSYIL PFSEVLDWKR 370 380 390 400 410 420 ASVVVPEEKM SDVYSILQSI PQRQIEEMQR QARWFWEAYF QSIKAIALAT LQIINDRIYP 430 440 450 460 470 480 YAAISYEEWN DPPAVKWGSV SNPLFLPLIP PQSQGFTAIV LTYDRVESLF RVITEVSKVP 490 500 510 520 530 540 SLSKLLVVWN NQNKNPPEDS LWPKIRVPLK VVRTAENKLS NRFFPYDEIE TEAVLAIDDD 550 560 570 580 590 600 IIMLTSDELQ FGYEVWREFP DRLVGYPGRL HLWDHEMNKW KYESEWTNEV SMVLTGAAFY 610 620 630 640 650 660 HKYFNYLYTY KMPGDIKNWV DAHMNCEDIA MNFLVANVTG KAVIKVTPRK KFKCPECTAI 670 680 690 700 710 DGLSLDQTHM VERSECINKF ASVFGTMPLK VVEHRADPVL YKDDFPEKLK SFPNIGSL
	Isoform 2. Checksum: BDAC3436BF9423D7		728	83,598
	10 20 30 40 50 60 MCASVKYNIR GPALIPRMKT KHRIYYITLF SIVLLGLIAT GMFQFWPHSI ESSNDWNVEK 70 80 90 100 110 120 RSIRDVPVVR LPADSPIPER GDLSCRMHTC FDVYRCGFNP KNKIKVYIYA LKKYVDDFGV 130 140 150 160 170 180 SVSNTISREY NELLMAISDS DYYTDDINRA CLFVPSIDVL NQNTLRIKET AQAMAQLSRW 190 200 210 220 230 240 DRGTNHLLFN MLPGGPPDYN TALDVPRDRA LLAGGGFSTW TYRQGYDVSI PVYSPLSAEV 250 260 270 280 290 300 DLPEKGPGPR QYFLLSSQVG LHPEYREDLE ALQVKHGESV LVLDKCTNLS EGVLSVRKRC 310 320 330 340 350 360 HKHQVFDYPQ VLQEATFCVV LRGARLGQAV LSDVLQAGCV PVVIADSYIL PFSEVLDWKR 370 380 390 400 410 420 ASVVVPEEKM SDVYSILQSI PQRQIEEMQR QLFMEPVRRE NWSAANHQMN SLIWPREQWD 430 440 450 460 470 480 SQIINDRIYP YAAISYEEWN DPPAVKWGSV SNPLFLPLIP PQSQGFTAIV LTYDRVESLF 490 500 510 520 530 540 RVITEVSKVP SLSKLLVVWN NQNKNPPEDS LWPKIRVPLK VVRTAENKLS NRFFPYDEIE 550 560 570 580 590 600 TEAVLAIDDD IIMLTSDELQ FGYEVWREFP DRLVGYPGRL HLWDHEMNKW KYESEWTNEV 610 620 630 640 650 660 SMVLTGAAFY HKYFNYLYTY KMPGDIKNWV DAHMNCEDIA MNFLVANVTG KAVIKVTPRK 670 680 690 700 710 720 KFKCPECTAI DGLSLDQTHM VERSECINKF ASVFGTMPLK VVEHRADPVL YKDDFPEKLK SFPNIGSL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes." Stickens D.J., Clines G., Burbee D.G., Ramos P., Thomas S., Hogue D., Hecht J.T., Lovett M., Evans G.A. Nat. Genet. 14:25-32(1996) [PubMed: 8782816] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Brain.
[2]	"Positional cloning of a gene involved in hereditary multiple exostoses." Wuyts W., van Hul W., Wauters J., Nemtsova M., Reyniers E., van Hul E., de Boulle K., de Vries B.B.A., Hendrickx J., Herrygers I., Bossuyt P., Balemans W., Fransen E., Vits L., Coucke P., Nowak N.J., Mallet L., van den Ouweland A.M.W. , McGaughran J., Halley D.J.J., Willems P.J. Hum. Mol. Genet. 5:1547-1557(1996) [PubMed: 8894688] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
[3]	"The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans." Clines G.A., Ashley J.A., Shah S., Lovett M. Genome Res. 7:359-367(1997) [PubMed: 9110175] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[4]	"Molecular cloning of a candidate gene for hereditary multiple exostoses type II." Deng H.-X., Fan C., Xia J.H., Xu L., He X.X., Ruan Q.G., Yang Y., Huang L. Prog. Nat. Sci. 6:692-699(1996) Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 2).
[5]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Ovary.
[6]	"Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus." Kobayashi S., Morimoto K., Shimizu T., Takahashi M., Kurosawa H., Shirasawa T. Biochem. Biophys. Res. Commun. 268:860-867(2000) [PubMed: 10679296] [Abstract] Cited for: SUBUNIT, SUBCELLULAR LOCATION.
[7]	"A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses." Simmons A.D., Musy M.M., Lopes C.S., Hwang L.-Y., Yang Y.-P., Lovett M. Hum. Mol. Genet. 8:2155-2164(1999) [PubMed: 10545594] [Abstract] Cited for: INTERACTION WITH GALNT5.
[8]	"Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes." Wuyts W., Van Hul W. Hum. Mutat. 15:220-227(2000) [PubMed: 10679937] [Abstract] Cited for: REVIEW ON VARIANTS.
[9]	"Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses." Philippe C., Porter D.E., Emerton M.E., Wells D.E., Simpson A.H.R.W., Monaco A.P. Am. J. Hum. Genet. 61:520-528(1997) [PubMed: 9326317] [Abstract] Cited for: VARIANT EXT2 ASN-227.
[10]	"Mutation analysis of hereditary multiple exostoses in the Chinese." Xu L., Xia J., Jiang H., Zhou J., Li H., Wang D., Pan Q., Long Z., Fan C., Deng H.-X. Hum. Genet. 105:45-50(1999) [PubMed: 10480354] [Abstract] Cited for: VARIANT EXT2 ARG-152, ALTERNATIVE SPLICING.
[11]	"Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses." Park K.J., Shin K.-H., Ku J.-L., Cho T.-J., Lee S.H., Choi I.H., Philippe C., Monaco A.P., Porter D.E., Park J.-G. J. Hum. Genet. 44:230-234(1999) [PubMed: 10429361] [Abstract] Cited for: VARIANT EXT2 ARG-85.
[12]	"An R223P mutation in EXT2 gene causes hereditary multiple exostoses." Shi Y.-R., Wu J.-Y., Tsai F.-J., Lee C.-C., Tsai C.-H. Hum. Mutat. 15:390-391(2000) [PubMed: 10738008] [Abstract] Cited for: VARIANT EXT2 PRO-223.
[13]	"Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses." Seki H., Kubota T., Ikegawa S., Haga N., Fujioka F., Ohzeki S., Wakui K., Yoshikawa H., Takaoka K., Fukushima Y. Am. J. Med. Genet. 99:59-62(2001) [PubMed: 11170095] [Abstract] Cited for: VARIANT EXT2 VAL-202.
[14]	"Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes." Bernard M.A., Hall C.E., Hogue D.A., Cole W.G., Scott A., Snuggs M.B., Clines G.A., Luedecke H.-J., Lovett M., Van Winkle W.B., Hecht J.T. Cell Motil. Cytoskeleton 48:149-162(2001) [PubMed: 11169766] [Abstract] Cited for: VARIANT EXT2 ASN-227.
[15]	"Ext-mutation analysis in Italian sporadic and hereditary osteochondromas." Gigante M., Matera M.G., Seripa D., Izzo A.M., Venanzi R., Giannotti A., Digilio M.C., Gravina C., Lazzari M., Monteleone G., Monteleone M., Dallapiccola B., Fazio V.M. Int. J. Cancer 95:378-383(2001) [PubMed: 11668521] [Abstract] Cited for: VARIANT EXT2 THR-380, VARIANT OSTEOCHONDROMA LYS-576.
[16]	"Genotype-phenotype correlation in hereditary multiple exostoses." Francannet C., Cohen-Tanugi A., Le Merrer M., Munnich A., Bonaventure J., Legeai-Mallet L. J. Med. Genet. 38:430-434(2001) [PubMed: 11432960] [Abstract] Cited for: VARIANTS EXT2 SER-179 AND ASN-227.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

GGDB

GlycoGene database

Cross-references

Sequence databases
EMBLGenBankDDBJ	U62740 mRNA. Translation: AAB07008.1. U64511 mRNA. Translation: AAC50764.1. U67368 , U67356, U67357, U67358, U67360, U67361, U67362, U67363, U67364, U67365, U67366, U67367 Genomic DNA. Translation: AAC51219.1. U72263 mRNA. Translation: AAB62718.1. BC010058 mRNA. Translation: AAH10058.1.
RefSeq	NP_000392.2. NP_997005.1.
UniGene	Hs.368404
3D structure databases
HSSP	HSSP built from PDB template 1OMX based on UniProtKB Q9ES89.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q93063. 10 interactions.
PTM databases
PhosphoSite	Q93063.
Proteomic databases
PRIDE	Q93063.
Genome annotation databases
Ensembl	ENSG00000151348. Homo sapiens. [Contig view]
GeneID	2132.
KEGG	hsa:2132.
Organism-specific databases
GeneCards	GC11P044073.
HGNC	HGNC:3513. EXT2.
MIM	133701. phenotype. 601224. phenotype. 608210. gene.
Orphanet	321. Exostoses, multiple. 52022. Potocki-Shaffer syndrome.
PharmGKB	PA27925.
GenAtlas	Search...
Phylogenomic databases
HOVERGEN	Q93063.
Gene expression databases
ArrayExpress	Q93063.
CleanEx	HS_EXT2.
GermOnline	ENSG00000151348. Homo sapiens.
Family and domain databases
InterPro	IPR004263. Exostosin. IPR015338. HexNAc_Trfase_a. [Graphical view]
Pfam	PF03016. Exostosin. 1 hit. PF09258. EXTL2. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	8615.
SOURCE	Search...

Entry information

Entry name

EXT2_HUMAN

Accession

Primary (citable) accession number: Q93063
Secondary accession number(s): O15288

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	February 1, 1997
Last modified:	December 16, 2008
This is version 85 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)