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GALNT6 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6))

Written2013-07Jae-Hyun Park, Yusuke Nakamura
Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesUDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6)
Alias_symbol (synonym)GalNAc-T6
Other aliasGALNAC-T6
GalNAcT6
HGNC (Hugo) GALNT6
LocusID (NCBI) 11226
Atlas_Id 50683
Location 12q13.13  [Link to chromosome band 12q13]
Location_base_pair Starts at 51745833 and ends at 51785200 bp from pter ( according to hg19-Feb_2009)  [Mapping GALNT6.png]
Fusion genes
(updated 2016)
C3 (19p13.3) / GALNT6 (12q13.13)GALNT6 (12q13.13) / GALNT6 (12q13.13)

DNA/RNA

Note GALNT6 is highly expressed in many types of cancer, but expression of GALNT6 is hardly detectable in human normal tissues (Park et al., 2010).
Description Human GALNT6 gene is located on 12 chromosome at q13.13 location. The GALNT6 gene is composed of 12 exons and ORF (open reading frame) is 1869 bp.

Protein

Note Human GALNT6 gene encodes 622 amino acids of 71159 Da. The protein is involved in the first step of O-type glycosylation by transferring UDP-GalNAc to Ser/Thr site of substrate protein. GALNT6 was firstly identified as a glycosyltransferase with high sequence similarity to GALNT3 (Bennett et al., 1999). GALNT6 has similar kinetic properties with other GALNTs but preferentially glycosylated fibronectin peptide in vitro. Because of expression in WI38 fibroblast cells, GALNT6 was regarded as a candidate for synthesis of the oncofetal fibronectin (Bennett et al., 1999). GALNT6 has two possible N-type glycosylation sites at N476 and N611.
 
  Functional domain of GALNT6. The protein contains signal peptide (1-34 aa), Gal/GalNAc transferase motif (180-370 aa), and ricin/lectin-like domain (496-622 aa).
Description The mucin-type O-glycosylation is initiated by GALNT family members that transfer N-acetyl-alpha-D-galactosamine (GalNAc) to serine or threonine residues on the target protein (Ten Hagen et al., 2003). This modification occurs in the Golgi complex and is presumably controlled by the expressions and distributions of GALNT proteins (Brooks et al., 2007). Interestingly, structural alterations of these glycan chains are often detected in cancer cells, especially in breast cancer. For instances, the O-glycans were often truncated (core 1-based type) in breast carcinoma cells, whereas they were extended its chain (core 2-based type) in normal breast cells (Burchell et al., 2001). O-type glycosylation is one of common modifications that have multiple functions related to the folding, stability, and targeting of various glycoproteins (Carraway et al., 2007). Accumulating evidences have suggested that the GALNT family members are involved in several cellular functions by catalyzing substrates specific to each member. For instances, glycosylation by GALNT3 prevents proteolytic processing of FGF23 (fibroblast growth factor 23) and that by GALNT14 promotes ligand-stimulated clustering of death receptors (Wagner et al., 2007; Ichikawa et al., 2009).
Expression GALNT6 is highly expressed in many types of cancer including breast, gastric, kidney, oral, and pancreatic cancer (Berois et al., 2006; Gomes et al., 2009; Kitada et al., 2013; Wandall et al., 2007; Li et al., 2011). However, in human normal tissues, GALNT6 is merely expressed in normal tissues and vital organs including lung, heart, liver, and kidney (Park et al., 2010). A specific expression of GALNT6 was also reported in the nonkeratinized epithelium of ocular cicatricial pemphigoid (OCP) patients (Argüeso et al., 2003).
Localisation Similarly to other isoforms in the GALNT family, GALNT6 is localized in the Golgi complex as shown by double immunofluorescence staining with anti-GALNT6 mAb and anti-Golgi-58k mAb (Park et al., 2010).
Function GALNT6 is involved in the first step of O-type glycosylation, and thereby may influence on folding, stability, and subcellular localization of target proteins. GALNT6 was reported to stabilize MUC1 protein throughout O-glycosylation and subsequently the accumulated MUC1 protein promoted breast cancer cell proliferation and induced anti-adhesive effects (Park et al., 2010). By O-glycosylation of fibronectin protein, GALNT6 showed transformational potentials through disruptive acinar morphogenesis and cellular changes similar to EMT (epithelial-to-mesenchymal transition) in normal mammary epithelial cell (Park et al., 2011). The GALNT6-mediated O-glycosylation of fibronectin was also reported in the TGF-β-induced EMT process in human prostate cells (Freire-de-Lima et al., 2011).
Homology GALNT6 has 30~63% of amino acid homology with other family members, with the highest homology to GALNT3 (63%). In crystal structure analysis of murine GALNT isoforms, GALNT1 was reported to be more similar to GALNT6 according to the electrostatic surface potential models (Fritz et al., 2004).

Implicated in

Note
  
Entity Breast cancer
Note High expression of GALNT6 was frequently observed in human breast cancers (Berois et al., 2006; Freire et al., 2006; Patani et al., 2008; Park et al., 2010). In particular, strong expression of GALNT6 was reported in most of DCIS (ductal carcinoma in situ) indicating that GALNT6 should play important roles in early human breast carcinogenesis (Berois et al., 2006). On the other hand, a study of metastatic breast cancer showed that GALNT6 expression was frequently detected in bone marrow biopsy samples and therefore suggested that GALNT6 would be a good target for detection of disseminated breast cancer cells (Freire et al., 2006).
Prognosis Disease free survival was elongated in breast cancer patients who showed negative expression of GALNT6 from bone marrow biopsy (Freire et al., 2006).
  
  
Entity Gastric cancer
Note High expression of GALNT6 was reported in human gastric cancers. A heterogeneous expression and staining pattern of GALNT6 was observed in 79% of gastric carcinomas, and its expression level was associated with the presence of venous invasion (Gomes et al., 2009).
  
  
Entity Oral cancer
Note GALNT6 was expressed in the oral squamous carcinoma cells, but not expressed in normal stromal fibroblasts (Wandall et al., 2007).
  
  
Entity Pancreatic cancer
Note GALNT6 was highly expressed in pancreatic cancer, but not expressed in normal ductal epithelium. A close relationship was noted between GALNT6-positive expression and pathological well/moderate differentiated type, small tumor size, and absence of vascular invasion (Li et al., 2011).
Prognosis In contrast to other reports, the outcome of the patients who had GALNT6-positive expression was significantly better than that with GALNT6-negative expression, especially in the early period after surgery (Li et al., 2011).
  
  
Entity Renal cell carcinoma
Note GALNT6 was weakly expressed in 64 out of 254 renal cell carcinomas (Kitada et al., 2013).
Prognosis GALNT6-positive patients showed poor prognosis with lower disease-specific survival rate (Kitada et al., 2013).
  
  
Entity Ocular cicatricial pemphigoid (OCP)
Note OCP is one of the subsets of mucous membrane pemphigoid, which may be caused by aberrant synthesis of mucin O-glycans and thus by alteration of the physicochemical properties of mucins. GALNT6 was expressed in the apical stratified epithelia, but specific expression of GALNT6 was detected in nonkeratinized epithelium of OCP patients, without expression in keratinized epithelium nor normal subjects (Argüeso et al., 2003).
  

Bibliography

The cell-layer- and cell-type-specific distribution of GalNAc-transferases in the ocular surface epithelia is altered during keratinization.
Argueso P, Tisdale A, Mandel U, Letko E, Foster CS, Gipson IK.
Invest Ophthalmol Vis Sci. 2003 Jan;44(1):86-92.
PMID 12506059
 
Cloning and characterization of a close homologue of human UDP-N-acetyl-alpha-D-galactosamine:Polypeptide N-acetylgalactosaminyltransferase-T3, designated GalNAc-T6. Evidence for genetic but not functional redundancy.
Bennett EP, Hassan H, Mandel U, Hollingsworth MA, Akisawa N, Ikematsu Y, Merkx G, van Kessel AG, Olofsson S, Clausen H.
J Biol Chem. 1999 Sep 3;274(36):25362-70.
PMID 10464263
 
UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-6 as a new immunohistochemical breast cancer marker.
Berois N, Mazal D, Ubillos L, Trajtenberg F, Nicolas A, Sastre-Garau X, Magdelenat H, Osinaga E.
J Histochem Cytochem. 2006 Mar;54(3):317-28. Epub 2005 Oct 31.
PMID 16260590
 
Immunolocalisation of members of the polypeptide N-acetylgalactosaminyl transferase (ppGalNAc-T) family is consistent with biologically relevant altered cell surface glycosylation in breast cancer.
Brooks SA, Carter TM, Bennett EP, Clausen H, Mandel U.
Acta Histochem. 2007;109(4):273-84. Epub 2007 Apr 19.
PMID 17448526
 
O-linked glycosylation in the mammary gland: changes that occur during malignancy.
Burchell JM, Mungul A, Taylor-Papadimitriou J.
J Mammary Gland Biol Neoplasia. 2001 Jul;6(3):355-64. (REVIEW)
PMID 11547903
 
Contribution of membrane mucins to tumor progression through modulation of cellular growth signaling pathways.
Carraway KL 3rd, Funes M, Workman HC, Sweeney C.
Curr Top Dev Biol. 2007;78:1-22. (REVIEW)
PMID 17338913
 
UDP-N-acetyl-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 6 (ppGalNAc-T6) mRNA as a potential new marker for detection of bone marrow-disseminated breast cancer cells.
Freire T, Berois N, Sonora C, Varangot M, Barrios E, Osinaga E.
Int J Cancer. 2006 Sep 15;119(6):1383-8.
PMID 16596643
 
Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process.
Freire-de-Lima L, Gelfenbeyn K, Ding Y, Mandel U, Clausen H, Handa K, Hakomori SI.
Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17690-5. doi: 10.1073/pnas.1115191108. Epub 2011 Oct 17.
PMID 22006308
 
The beginnings of mucin biosynthesis: the crystal structure of UDP-GalNAc:polypeptide alpha-N-acetylgalactosaminyltransferase-T1.
Fritz TA, Hurley JH, Trinh LB, Shiloach J, Tabak LA.
Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15307-12. Epub 2004 Oct 14.
PMID 15486088
 
Expression of UDP-N-acetyl-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase-6 in gastric mucosa, intestinal metaplasia, and gastric carcinoma.
Gomes J, Marcos NT, Berois N, Osinaga E, Magalhaes A, Pinto-de-Sousa J, Almeida R, Gartner F, Reis CA.
J Histochem Cytochem. 2009 Jan;57(1):79-86. doi: 10.1369/jhc.2008.952283. Epub 2008 Oct 14.
PMID 18854599
 
Ablation of the Galnt3 gene leads to low-circulating intact fibroblast growth factor 23 (Fgf23) concentrations and hyperphosphatemia despite increased Fgf23 expression.
Ichikawa S, Sorenson AH, Austin AM, Mackenzie DS, Fritz TA, Moh A, Hui SL, Econs MJ.
Endocrinology. 2009 Jun;150(6):2543-50. doi: 10.1210/en.2008-0877. Epub 2009 Feb 12.
PMID 19213845
 
Polypeptide N-acetylgalactosaminyl transferase 3 independently predicts high-grade tumours and poor prognosis in patients with renal cell carcinomas.
Kitada S, Yamada S, Kuma A, Ouchi S, Tasaki T, Nabeshima A, Noguchi H, Wang KY, Shimajiri S, Nakano R, Izumi H, Kohno K, Matsumoto T, Sasaguri Y.
Br J Cancer. 2013 Jul 23;109(2):472-81. doi: 10.1038/bjc.2013.331. Epub 2013 Jun 25.
PMID 23799843
 
Polypeptide N-acetylgalactosaminyltransferase 6 expression in pancreatic cancer is an independent prognostic factor indicating better overall survival.
Li Z, Yamada S, Inenaga S, Imamura T, Wu Y, Wang KY, Shimajiri S, Nakano R, Izumi H, Kohno K, Sasaguri Y.
Br J Cancer. 2011 Jun 7;104(12):1882-9. doi: 10.1038/bjc.2011.166. Epub 2011 May 17.
PMID 21587259
 
Polypeptide N-acetylgalactosaminyltransferase 6 disrupts mammary acinar morphogenesis through O-glycosylation of fibronectin.
Park JH, Katagiri T, Chung S, Kijima K, Nakamura Y.
Neoplasia. 2011 Apr;13(4):320-6.
PMID 21472136
 
Critical roles of mucin 1 glycosylation by transactivated polypeptide N-acetylgalactosaminyltransferase 6 in mammary carcinogenesis.
Park JH, Nishidate T, Kijima K, Ohashi T, Takegawa K, Fujikane T, Hirata K, Nakamura Y, Katagiri T.
Cancer Res. 2010 Apr 1;70(7):2759-69. doi: 10.1158/0008-5472.CAN-09-3911. Epub 2010 Mar 9.
PMID 20215525
 
Prognostic utility of glycosyltransferase expression in breast cancer.
Patani N, Jiang W, Mokbel K.
Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):333-40.
PMID 19287074
 
All in the family: the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferases.
Ten Hagen KG, Fritz TA, Tabak LA.
Glycobiology. 2003 Jan;13(1):1R-16R. Epub 2002 Nov 1. (REVIEW)
PMID 12634319
 
Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL.
Wagner KW, Punnoose EA, Januario T, Lawrence DA, Pitti RM, Lancaster K, Lee D, von Goetz M, Yee SF, Totpal K, Huw L, Katta V, Cavet G, Hymowitz SG, Amler L, Ashkenazi A.
Nat Med. 2007 Sep;13(9):1070-7. Epub 2007 Sep 2.
PMID 17767167
 
Molecular basis for the presence of glycosylated onco-foetal fibronectin in oral carcinomas: the production of glycosylated onco-foetal fibronectin by carcinoma cells.
Wandall HH, Dabelsteen S, Sorensen JA, Krogdahl A, Mandel U, Dabelsteen E.
Oral Oncol. 2007 Mar;43(3):301-9. Epub 2006 Jul 20.
PMID 16857413
 

Citation

This paper should be referenced as such :
Park, JH ; Nakamura, Y
GALNT6 (UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 6 (GalNAc-T6))
Atlas Genet Cytogenet Oncol Haematol. 2014;18(2):90-92.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/GALNT6ID50683ch12q13.html


External links

Nomenclature
HGNC (Hugo)GALNT6   4128
Cards
AtlasGALNT6ID50683ch12q13
Entrez_Gene (NCBI)GALNT6  11226  polypeptide N-acetylgalactosaminyltransferase 6
AliasesGALNAC-T6; GalNAcT6
GeneCards (Weizmann)GALNT6
Ensembl hg19 (Hinxton)ENSG00000139629 [Gene_View]  chr12:51745833-51785200 [Contig_View]  GALNT6 [Vega]
Ensembl hg38 (Hinxton)ENSG00000139629 [Gene_View]  chr12:51745833-51785200 [Contig_View]  GALNT6 [Vega]
ICGC DataPortalENSG00000139629
TCGA cBioPortalGALNT6
AceView (NCBI)GALNT6
Genatlas (Paris)GALNT6
WikiGenes11226
SOURCE (Princeton)GALNT6
Genetics Home Reference (NIH)GALNT6
Genomic and cartography
GoldenPath hg19 (UCSC)GALNT6  -     chr12:51745833-51785200 -  12q13   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)GALNT6  -     12q13   [Description]    (hg38-Dec_2013)
EnsemblGALNT6 - 12q13 [CytoView hg19]  GALNT6 - 12q13 [CytoView hg38]
Mapping of homologs : NCBIGALNT6 [Mapview hg19]  GALNT6 [Mapview hg38]
OMIM605148   
Gene and transcription
Genbank (Entrez)AB265820 AK025961 AK074658 AK092496 AK296852
RefSeq transcript (Entrez)NM_007210
RefSeq genomic (Entrez)NC_000012 NC_018923 NT_029419 NW_004929384
Consensus coding sequences : CCDS (NCBI)GALNT6
Cluster EST : UnigeneHs.505575 [ NCBI ]
CGAP (NCI)Hs.505575
Alternative Splicing GalleryENSG00000139629
Gene ExpressionGALNT6 [ NCBI-GEO ]   GALNT6 [ EBI - ARRAY_EXPRESS ]   GALNT6 [ SEEK ]   GALNT6 [ MEM ]
Gene Expression Viewer (FireBrowse)GALNT6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)11226
GTEX Portal (Tissue expression)GALNT6
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ8NCL4   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ8NCL4  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ8NCL4
Splice isoforms : SwissVarQ8NCL4
Catalytic activity : Enzyme2.4.1.41 [ Enzyme-Expasy ]   2.4.1.412.4.1.41 [ IntEnz-EBI ]   2.4.1.41 [ BRENDA ]   2.4.1.41 [ KEGG ]   
PhosPhoSitePlusQ8NCL4
Domaine pattern : Prosite (Expaxy)RICIN_B_LECTIN (PS50231)   
Domains : Interpro (EBI)Glyco_trans_2-like    Nucleotide-diphossugar_trans    Ricin_B_lectin   
Domain families : Pfam (Sanger)Glycos_transf_2 (PF00535)    Ricin_B_lectin (PF00652)   
Domain families : Pfam (NCBI)pfam00535    pfam00652   
Domain families : Smart (EMBL)RICIN (SM00458)  
Conserved Domain (NCBI)GALNT6
DMDM Disease mutations11226
Blocks (Seattle)GALNT6
SuperfamilyQ8NCL4
Human Protein AtlasENSG00000139629
Peptide AtlasQ8NCL4
HPRD05512
IPIIPI00026991   IPI00792848   
Protein Interaction databases
DIP (DOE-UCLA)Q8NCL4
IntAct (EBI)Q8NCL4
FunCoupENSG00000139629
BioGRIDGALNT6
STRING (EMBL)GALNT6
ZODIACGALNT6
Ontologies - Pathways
QuickGOQ8NCL4
Ontology : AmiGOGolgi membrane  polypeptide N-acetylgalactosaminyltransferase activity  Golgi apparatus  protein O-linked glycosylation  integral component of membrane  O-glycan processing  carbohydrate binding  metal ion binding  perinuclear region of cytoplasm  
Ontology : EGO-EBIGolgi membrane  polypeptide N-acetylgalactosaminyltransferase activity  Golgi apparatus  protein O-linked glycosylation  integral component of membrane  O-glycan processing  carbohydrate binding  metal ion binding  perinuclear region of cytoplasm  
Pathways : KEGGMucin type O-Glycan biosynthesis   
REACTOMEQ8NCL4 [protein]
REACTOME Pathways913709 [pathway]   
NDEx NetworkGALNT6
Atlas of Cancer Signalling NetworkGALNT6
Wikipedia pathwaysGALNT6
Orthology - Evolution
OrthoDB11226
GeneTree (enSembl)ENSG00000139629
Phylogenetic Trees/Animal Genes : TreeFamGALNT6
HOVERGENQ8NCL4
HOGENOMQ8NCL4
Homologs : HomoloGeneGALNT6
Homology/Alignments : Family Browser (UCSC)GALNT6
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerGALNT6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)GALNT6
dbVarGALNT6
ClinVarGALNT6
1000_GenomesGALNT6 
Exome Variant ServerGALNT6
ExAC (Exome Aggregation Consortium)GALNT6 (select the gene name)
Genetic variants : HAPMAP11226
Genomic Variants (DGV)GALNT6 [DGVbeta]
DECIPHER (Syndromes)12:51745833-51785200  ENSG00000139629
CONAN: Copy Number AnalysisGALNT6 
Mutations
ICGC Data PortalGALNT6 
TCGA Data PortalGALNT6 
Broad Tumor PortalGALNT6
OASIS PortalGALNT6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICGALNT6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDGALNT6
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch GALNT6
DgiDB (Drug Gene Interaction Database)GALNT6
DoCM (Curated mutations)GALNT6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)GALNT6 (select a term)
intoGenGALNT6
NCG5 (London)GALNT6
Cancer3DGALNT6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM605148   
Orphanet
MedgenGALNT6
Genetic Testing Registry GALNT6
NextProtQ8NCL4 [Medical]
TSGene11226
GENETestsGALNT6
Huge Navigator GALNT6 [HugePedia]
snp3D : Map Gene to Disease11226
BioCentury BCIQGALNT6
ClinGenGALNT6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD11226
Chemical/Pharm GKB GenePA28541
Clinical trialGALNT6
Miscellaneous
canSAR (ICR)GALNT6 (select the gene name)
Probes
Litterature
PubMed13 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineGALNT6
EVEXGALNT6
GoPubMedGALNT6
iHOPGALNT6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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