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GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type)

Written2007-11Prakash Radhakrishnan, Pi-Wan Cheng
Department of Biochemistry, Molecular Biology, College of Medicine, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-5870, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)C2GnT-M
C2/4GnT
C2GnT2
Other aliashC2GnT-M
C2/C4gnT
GnT-M
mucus type C2GnT
HGNC (Hugo) GCNT3
LocusID (NCBI) 9245
Atlas_Id 44105
Location 15q22.2  [Link to chromosome band 15q22]
Location_base_pair Starts at 59611783 and ends at 59620011 bp from pter ( according to hg19-Feb_2009)  [Mapping GCNT3.png]
Fusion genes
(updated 2016)
GCNT3 (15q22.2) / HSP90B1 (12q23.3)
Note GCNT3/C2GnT-M is a single pass type II membrane protein belonging to glycosyltransferase 14 family.

DNA/RNA

Note Human GCNT3/C2GnT-M is located on chromosome 15 in the region of q21.3, oriented from centromere to telomere.
 
  Schematic representation of Human GCNT3/C2GnT-M gene and transcripts. There are three different sized transcripts. (TIS, Transcription Initiation Site designated as +1; E, Exon; I, Intron; UTR, Untranslated region; ATG, start codon; ORF, Open reading frame).
Description Human GCNT3/C2GnT-M gene is approximatively 8.26 kb in size and located in chromosome 15q21.3 at the position of 57,691,415 - 57,699,501. Recently, the GCNT3/C2GnT-M promoter (-417/+187) containing two basal cis-regulatory region (-291/-182 and -62/-43) was identified. The Th2 cytokine and retinoic acid responsive cis-regulatory elements reside in -417/+187 region.
Transcription Human GCNT3/C2GnT-M contains three different sized transcripts: 2.3-2.5, 3.6-3.8 and 6.8-7.0 kb. The transcript 1 (approximatively 2.3-2.5kb) is made of 3 exons, exon 1 (69-198 bp), exon 2 (333-401 bp), and exon 3 (1864 bp). Exon 3 contains 59 bp of 5' UTR, 1314 bp of ORF and 491 bp of 3'UTR. It does not contain any introns. Whereas, the intermediate sized transcript (3.6-3.8kb) contains 1.3kb of intron 2 and the large sized transcript (6.8-7.0 kb) contains 4.5kb of intron 1 in addition to all three exons. Exon 1 is heterogeneous in size, which ranges from 69 to 198 bp depending on tissues and cells. Exon 1 is present in all transcripts and has same 3' end but different 5' ends. A 333 bp Exon 2 is identified in most of the mucus secreting tissues and airway epithelial cells while a 401 bp of exon 2 is only detected in A549 cells.

Protein

Note Human GCNT3/C2GnT-M (EC 2.4.1.102) has 438 amino acids and molecular weight of 50,863 Da.
 
  The predicted GCNT3/C2GnT-M structure shows a short N-terminal cytoplasmic tail (CT), a transmembrane domain (TM), a stem region and a long catalytic domain at the C-terminal region.
Description GCNT3/C2GnT-M is a type II membrane protein located in the Golgi apparatus. It contains a nine-amino acid peptide tail at the N-terminus located in the cytoplasm, which is followed by a transmembrane domain consisted of 18 amino acids, a stem region, and a catalytic domain located in the Golgi lumen. The protein contains 13 cysteines, including 4 at the N-terminal region, which are conserved among GCNT3/C2GnT-M across species, and 9 at the C-terminal region, which are conserved among all mucin glycan b6GlcNAc branching enzymes. Structural information obtained from bovine GCNT3/C2GnT-M shows that among the 9 conserved cysteines, the second cysteine is unconjugated and the other 8 cysteines form 4 cystine bonds between first and ninth, third and seventh, fourth and fifth, and sixth and eighth. The disulfide bonds formed from the nine conserved cysteines are different between GCNT3/C2GnT-M and C2GnT-L. GCNT3/C2GnT-M contains two potential N-glycosyltaion sites at N-69 and N-289.
Expression Human GCNT3/C2GnT-M gene is expressed in mucus-secretory tissues in the following decreasing order of expression: Colon; testis; stomach; small intestine; adrenal gland; kidney; trachea; thyroid gland; Uterus; Ovary; Pancreas; fetal liver; Prostate. Unlike bovine GCNT3/C2GnT-M gene, the type of transcript expressed by hC2GnT-M gene is not tissue specific among the mucus secretory tissues. Expression of GCNT3/C2GnT-M gene is down regulated in colon and colorectal tumors and various colorectal cancer cells. GCNT3/C2GnT-M expression is regulated by various external agent(s). It is inhibited by EGF and enhanced by Th2 cytokines, retinoic acids and sodium butyrate.
Localisation Golgi membrane.
Function GCNT3/C2GnT-M is responsible for the synthesis of all three branch structures, including core 2, core 4, and I antigen found in the glycans of secreted mucins. These three branch structures are generated by the transfer of GlcNAc from UDP-GlcNAc to core 1, core 3, and I antigen, respectively as shown below.
1. UDP-GlcNAc + Galbeta1-3GalNAca1-S/T gives Galbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP
2. UDP-GlcNAc + GlcNAcbeta1-3GalNAc1a-S/T gives GlcNAcbeta1-3(GlcNAcbeta1-6) GalNAca1-S/T + UDP
3. UDP-GlcNAc + GlcNAcbeta1-3Galbeta1-R gives GlcNAcbeta1-3(GlcNAcbeta1-6)Galbeta1-R + UDP(R: sugars)
The primary function of secreted mucins is to protect mucus secretory epithelium by retention of water and maintenance of the rheological properties of the mucus, and adherence to airborne and ingested pathogens to facilitate their removal from these tissues. The first two properties depend primarily on the carbohydrate content and this property depends on the heterogeneity of carbohydrate structure. Secreted mucins contain very high carbohydrate content, i.e. 70-90% by weight, and very heterogeneous carbohydrate structure, e.g. up to 100 different oligosaccharides in mucins isolated from a single donor. The three b6GlcNAc branch structures found in the secreted mucins are responsible for the increase of carbohydrate content and structural complexity. Decrease of GCNT3/C2GnT-M in the secretory epithelium can result in dehydration of the mucus and compromise of bacterial clearance.
Homology Human GCNT3/C2GnT-M shows a very high level of similarity to other non-human GCNT3/C2GnT-M: bovine (83%), rat (78%) and mouse (77%). Further, it shows moderate level of (48% and 38%) similarity to human C2GnT-L and C2GnT-T, respectively.

Implicated in

Note
  
Entity Colorectal cancer
Note GCNT3/C2GnT-M enzyme is down regulated in colon and colorectal tumors and most cancerous cells derived from mucus-secretory tissues. Re-expression of GCNT3/C2GnT-M suppresses tumor growth in the xenografts of nude mice.
Disease Colorectal cancer is the 3rd most common form of cancer and the 2nd leading cause of cancer-related death among men and women in the Western world. It causes 655,000 deaths worldwide per year. The survival rate of colorectal cancer is not much higher than 50% even if the disease is diagnosed at an early stage. Colorectal cancer is mostly formed from adenomatous polyps. These polyps can be detected and removed during colonoscopy, which would decrease cancer death by greater than 80%. Metastasis of cancer cells through bowel wall of the colon to lymph nodes is very common. If metastasis is detected, 5 year survival rate is less than 10%.
Prognosis Recent reports suggest that deficiency or down regulation of human GCNT3/C2GnT-M expression is associated with development of colitis and colorectal cancer. This enzyme may be used as a prognostic marker for colorectal cancer.
Oncogenesis GCNT3/C2GnT-M expression is down regulated in colorectal cancers. Down regulation of GCNT3/C2GnT-M would lead to the production of secreted mucins with lower carbohydrate content and less heterogeneous carbohydrate, which would compromise the protective function of these mucins. As a result, bacteria can not be cleared effectively, which causes irritation of the epithelium and chronic inflammation, and eventually cancer. Its re-expression suppresses tumor cell spreading, adhesion, motility, and invasion. It also inhibits cell growth and colony-forming ability, and induces apoptotic cell death. In addition, expression of C2GnT-M suppresses tumor growth in the xenografts of nude mice. The results suggest that GCNT3/C2GnT-M is important in protecting the normal functional architecture of colon epithelial cells.
  

Bibliography

Mucin biosynthesis: upregulation of core 2 beta 1,6 N-acetylglucosaminyltransferase by retinoic acid and Th2 cytokines in a human airway epithelial cell line.
Beum PV, Basma H, Bastola DR, Cheng PW
American journal of physiology. Lung cellular and molecular physiology. 2005 ; 288 (1) : L116-L124.
PMID 15591039
 
Biosynthesis and function of beta 1,6 branched mucin-type glycans.
Beum PV, Cheng PW
Advances in experimental medicine and biology. 2001 ; 491 : 279-312.
PMID 14533804
 
Mucin biosynthesis: molecular cloning and expression of mouse mucus-type core 2 beta1,6 N-acetylglucosaminyltransferase.
Hashimoto M, Tan S, Mori N, Cheng H, Cheng PW
Glycobiology. 2007 ; 17 (9) : 994-1006.
PMID 17591617
 
C2GnT-M is downregulated in colorectal cancer and its re-expression causes growth inhibition of colon cancer cells.
Huang MC, Chen HY, Huang HC, Huang J, Liang JT, Shen TL, Lin NY, Ho CC, Cho IM, Hsu SM
Oncogene. 2006 ; 25 (23) : 3267-3276.
PMID 16418723
 
Regulation of sialyl-Lewis x epitope expression by TNF-alpha and EGF in an airway carcinoma cell line.
Ishibashi Y, Inouye Y, Okano T, Taniguchi A
Glycoconjugate journal. 2005 ; 22 (1-2) : 53-62.
PMID 15864435
 
Butyrate induces sLex synthesis by stimulation of selective glycosyltransferase genes.
Radhakrishnan P, Beum PV, Tan S, Cheng PW
Biochemical and biophysical research communications. 2007 ; 359 (3) : 457-462.
PMID 17553459
 
Control of O-glycan branch formation. Molecular cloning of human cDNA encoding a novel beta1,6-N-acetylglucosaminyltransferase forming core 2 and core 4.
Schwientek T, Nomoto M, Levery SB, Merkx G, van Kessel AG, Bennett EP, Hollingsworth MA, Clausen H
The Journal of biological chemistry. 1999 ; 274 (8) : 4504-4512.
PMID 9988682
 
Identification of disulfide bonds among the nine core 2 N-acetylglucosaminyltransferase-M cysteines conserved in the mucin beta6-N-acetylglucosaminyltransferase family.
Singh J, Khan GA, Kinarsky L, Cheng H, Wilken J, Choi KH, Bedows E, Sherman S, Cheng PW
The Journal of biological chemistry. 2004 ; 279 (37) : 38969-38977.
PMID 15226299
 
Mucin biosynthesis: identification of the cis-regulatory elements of human C2GnT-M gene.
Tan S, Cheng PW
American journal of respiratory cell and molecular biology. 2007 ; 36 (6) : 737-745.
PMID 17303715
 
Molecular cloning and expression of a novel beta-1, 6-N-acetylglucosaminyltransferase that forms core 2, core 4, and I branches.
Yeh JC, Ong E, Fukuda M
The Journal of biological chemistry. 1999 ; 274 (5) : 3215-3221.
PMID 9915862
 

Citation

This paper should be referenced as such :
Radhakrishnan, P ; Cheng, PW
GCNT3 (glucosaminyl (N-acetyl) transferase 3, mucin type)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):276-278.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/GCNT3ID44105ch15q21.html


External links

Nomenclature
HGNC (Hugo)GCNT3   4205
Cards
AtlasGCNT3ID44105ch15q21
Entrez_Gene (NCBI)GCNT3  9245  glucosaminyl (N-acetyl) transferase 3, mucin type
AliasesC2/4GnT; C24GNT; C2GNT2; C2GNTM; 
GNTM
GeneCards (Weizmann)GCNT3
Ensembl hg19 (Hinxton)ENSG00000140297 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000140297 [Gene_View]  chr15:59611783-59620011 [Contig_View]  GCNT3 [Vega]
ICGC DataPortalENSG00000140297
TCGA cBioPortalGCNT3
AceView (NCBI)GCNT3
Genatlas (Paris)GCNT3
WikiGenes9245
SOURCE (Princeton)GCNT3
Genetics Home Reference (NIH)GCNT3
Genomic and cartography
GoldenPath hg38 (UCSC)GCNT3  -     chr15:59611783-59620011 +  15q22.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)GCNT3  -     15q22.2   [Description]    (hg19-Feb_2009)
EnsemblGCNT3 - 15q22.2 [CytoView hg19]  GCNT3 - 15q22.2 [CytoView hg38]
Mapping of homologs : NCBIGCNT3 [Mapview hg19]  GCNT3 [Mapview hg38]
OMIM606836   
Gene and transcription
Genbank (Entrez)AF038650 AF102542 AK312852 BC017032 BP243086
RefSeq transcript (Entrez)NM_004751
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)GCNT3
Cluster EST : UnigeneHs.194710 [ NCBI ]
CGAP (NCI)Hs.194710
Alternative Splicing GalleryENSG00000140297
Gene ExpressionGCNT3 [ NCBI-GEO ]   GCNT3 [ EBI - ARRAY_EXPRESS ]   GCNT3 [ SEEK ]   GCNT3 [ MEM ]
Gene Expression Viewer (FireBrowse)GCNT3 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)9245
GTEX Portal (Tissue expression)GCNT3
Protein : pattern, domain, 3D structure
UniProt/SwissProtO95395   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtO95395  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProO95395
Splice isoforms : SwissVarO95395
Catalytic activity : Enzyme2.4.1.102 [ Enzyme-Expasy ]   2.4.1.1022.4.1.102 [ IntEnz-EBI ]   2.4.1.102 [ BRENDA ]   2.4.1.102 [ KEGG ]   
PhosPhoSitePlusO95395
Domains : Interpro (EBI)Glyco_trans_14   
Domain families : Pfam (Sanger)Branch (PF02485)   
Domain families : Pfam (NCBI)pfam02485   
Conserved Domain (NCBI)GCNT3
DMDM Disease mutations9245
Blocks (Seattle)GCNT3
SuperfamilyO95395
Human Protein AtlasENSG00000140297
Peptide AtlasO95395
HPRD06018
IPIIPI00006248   
Protein Interaction databases
DIP (DOE-UCLA)O95395
IntAct (EBI)O95395
FunCoupENSG00000140297
BioGRIDGCNT3
STRING (EMBL)GCNT3
ZODIACGCNT3
Ontologies - Pathways
QuickGOO95395
Ontology : AmiGOGolgi membrane  immunoglobulin production in mucosal tissue  beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase activity  carbohydrate metabolic process  protein O-linked glycosylation  N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase activity  membrane  integral component of membrane  O-glycan processing  acetylgalactosaminyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase activity  tissue morphogenesis  intestinal absorption  kidney morphogenesis  extracellular exosome  
Ontology : EGO-EBIGolgi membrane  immunoglobulin production in mucosal tissue  beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase activity  carbohydrate metabolic process  protein O-linked glycosylation  N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase activity  membrane  integral component of membrane  O-glycan processing  acetylgalactosaminyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase activity  tissue morphogenesis  intestinal absorption  kidney morphogenesis  extracellular exosome  
Pathways : KEGGMucin type O-Glycan biosynthesis   
REACTOMEO95395 [protein]
REACTOME PathwaysR-HSA-913709 [pathway]   
NDEx NetworkGCNT3
Atlas of Cancer Signalling NetworkGCNT3
Wikipedia pathwaysGCNT3
Orthology - Evolution
OrthoDB9245
GeneTree (enSembl)ENSG00000140297
Phylogenetic Trees/Animal Genes : TreeFamGCNT3
HOVERGENO95395
HOGENOMO95395
Homologs : HomoloGeneGCNT3
Homology/Alignments : Family Browser (UCSC)GCNT3
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGCNT3 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GCNT3
dbVarGCNT3
ClinVarGCNT3
1000_GenomesGCNT3 
Exome Variant ServerGCNT3
ExAC (Exome Aggregation Consortium)GCNT3 (select the gene name)
Genetic variants : HAPMAP9245
Genomic Variants (DGV)GCNT3 [DGVbeta]
DECIPHERGCNT3 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisGCNT3 
Mutations
ICGC Data PortalGCNT3 
TCGA Data PortalGCNT3 
Broad Tumor PortalGCNT3
OASIS PortalGCNT3 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGCNT3  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGCNT3
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch GCNT3
DgiDB (Drug Gene Interaction Database)GCNT3
DoCM (Curated mutations)GCNT3 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GCNT3 (select a term)
intoGenGCNT3
NCG5 (London)GCNT3
Cancer3DGCNT3(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM606836   
Orphanet
MedgenGCNT3
Genetic Testing Registry GCNT3
NextProtO95395 [Medical]
TSGene9245
GENETestsGCNT3
Target ValidationGCNT3
Huge Navigator GCNT3 [HugePedia]
snp3D : Map Gene to Disease9245
BioCentury BCIQGCNT3
ClinGenGCNT3
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD9245
Chemical/Pharm GKB GenePA28620
Clinical trialGCNT3
Miscellaneous
canSAR (ICR)GCNT3 (select the gene name)
Probes
Litterature
PubMed17 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGCNT3
EVEXGCNT3
GoPubMedGCNT3
iHOPGCNT3
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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