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HAS2 (hyaluronan synthase 2)

Written2009-03Diogo Escudero
University of Miami School of Medicine, Miami, Florida 33136, USA

(Note : for Links provided by Atlas : click)

Identity

Other aliasMGC126241
MGC126242
HGNC (Hugo) HAS2
LocusID (NCBI) 3037
Atlas_Id 412
Location 8q24.13  [Link to chromosome band 8q24]
Location_base_pair Starts at 121613031 and ends at 121641390 bp from pter ( according to hg19-Feb_2009)  [Mapping HAS2.png]
 
  HAS2 gene presented in the minus strand of chromosome 8.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
HAS2 (8q24.13) / HHLA1 (8q24.22)HAS2 (8q24.13) / PLAG1 (8q12.1)PLAG1 (8q12.1) / HAS2 (8q24.13)
Note HA Synthase 2 was first cloned in 1996 by Watanabe and Yamaguchi. The following year, Spicer et al. identified and localized the human HAS2 gene to chromosome 8q24.12.

DNA/RNA

Note Three independently expressed hyaluronan synthase genes have been identified in the human genome. HAS2 is present in chromosome 8q24.12, while HAS1 and HAS3 have been identified to loci 19q13.4 and 16q22.1 respectively.
Description The HAS2 gene encodes for a 552 amino acid product comprised of 4 exons. Translation starts at the first nucleotide of exon 2 while a discrete 5'-untranslated region (UTR) is formed in exon 1.
Transcription Hyaluronan is catalyzed by three membrane-embedded HA synthases, although HAS2 is the only essential gene. The isozymes are coded by 3 separate genes that, although related, are unlinked in the chromosome. Regulation occurs at transcription, post-translational levels, as well as, by alternative splicing, differential sub-cellular localization and epigenetic processes. Hyaluronan deposits in the extracellular matrix have been associated with a variety of cellular processes such as motility, adhesion, division, morphogenesis, wound healing and vascular development. HAS2 overexpression, as well as, amplification of locus 8q24.12, has been implicated in tumor proliferation and metastasis in genitourinary tumors. Recently, the degree to which HA synthases can overexpressed has suggested the likelihood the gene may play contradicting roles as tumor suppressor and oncogene.

Protein

Note HAS2, a member of the glycosyl transferase family 2 proteins, is a multipass transmembrane protein that catalyses the polymerization of the integral extrecellular matrix component Hyaluronic acid from intracellular UDP-esterified precursor, resulting in glucuronic acid and N-acetylglucosamine dissacharide motifs.
 
  Illustration of HAS multipass transmembrane isozymes and their products.
Description HAS2 is one of the three characterized HA synthases responsible for the polymerization of Hyaluronic Acid in the extracellular matrix and is the only essential gene of the family. Although all three isozymes are equally capable of synthesizing HA polymers, it has been shown that HAS2 is the main HA synthase polymerizing long hyaluronan chains of MW ~2x106 Daltons.
Expression The extent of HAS2 expression and catalytic activity has been linked to specific interactions between the extracellular hyaluronan and the HA receptors, CD44 and RHAMM, distributed in the plasma membrane. The underlying signaling pathways regulating HAS2 expression have not been fully characterized. A number of distinctively regulated factors have been associated with HA deposition and HAS2 expression such as IL-1beta, NF-kappaB, all-trans-Retinoic Acid, SP1, Ras, TGF-beta1 among many others.
Localisation HAS2 is localized in the plasma membrane as a multipass transmembrane protein. Although it has been suggested the human HAS2 may share the same proposed topological domains as its bacterial counterpart, the extent to which this statement trully represents its actual architecture has not yet been shown.
Function Hyaluronan synthase 2 is responsible for the synthesis and deposition of hyaluronan in the extracellular matrix. HAS2 is a member of the glycosyl transferase 2 protein family and catalyses the addition of UDP-esterified residues, to form glucuronic acid and N-acetylglucosamine dissacharide motifs present in HA molecules. Interactions between plasma membrane embedded HA receptors with hyaluronan in the cellular matrix have been suggested to either induce or repress HAS2's catalytic activity. The presence of hyaluronan in the extracellular matrix has been linked to a great number of vital cellular processes such cell division, motility and morphogenesis, among many others. HAS2 is either an oncogene or a tumor suppressor depending on the concentration and length of HA products deposited in the extracellular matrix. Long HA chains of high molecular weight in high concentrations have been linked with supressing angiogenesis and tumor proliferation, whereas 2-3 fold HAS2 overexpression has been implicated in the proliferation and metastasis in various genitourinary tumor types.
Homology A total of 3 mammalian HAS genes have been isolated and identified (HAS1, HAS2, HAS3). Although they share similar amino acid sequences and structural conformations, each isozyme present different spacial and temporal expression patterns, molecular stability, kinetic properties and ability of yielding hyaluronan chains different in length and concentration.

Mutations

Note Developmental studies have described mutations disrupting HAS2 synthesis as embryonic lethal. Such mutations prevent cardiac endothelial to mesenchymal transition, resulting in failed heart morphogenesis.

Implicated in

Note
  
Entity Various cancer
Note Studies dating over 50 years have suggested an association between the increasing deposition of HA and tumors. Because hyaluronan is associated with such a variety of important biological cellular processes, it has been suggested that the abnormal overexpression of HAS2, among the other HA synthases, as well as deposition of HA in the extracellular matrix account for hijacked pathways to stimulate cell growth, proliferation, angiogenesis and metastasis in cancer cells. The use of pharmacological agents affecting HAS2 activity, as well as, HA breakdown in cancer treatment are promising. Recent studies suggest that tumor cells become less aggressive and proliferative when HA synthase is being suppressed or overexpressed in high concentrations. Diagnostic tests have been developed assaying for concentration of deposited hyaluronan as a tumor marker. The HA-Hase test, for example, is a sensitive and accurate diagnostic test for bladder cancer measuring the concentrations of hyaluronan and hyaluronidase (HA degrading protein) present in urine samples.
Disease Dysfunctional expression of HAS2 has been published in many genitourinary tumors, such as prostate cancer, testicular cancer and bladder cancer. This altered expression has been linked with chromosomal locus 8q24 amplification as well as deregulated HAS2 transcription, which have been shown to follow tumor progression.
Prognosis Histological studies, using specific hyaluronan affinity probes, suggest that all human epithelial tumors are associated with elevated amounts of hyaluronan in the extracellular matrix. Consequently, overexpression of HAS2 has been observed in various types of cancer. The presence of tumor associated hyaluronan has been observed in prostate cancer cells of high Gleason scores and matastasis, indicating poor prognosis. Also, primary tumor invasiveness and elevated PSA recurrence after surgical tumor removal have been correlated with strong stromal hyaluronan staining in radical prostatectomy specimens.
  
  
Entity Vascular disease
Disease Changes in the concentration and cellular distribution of HA have been observed in vascular diseases such as atherosclerosis, restenotic lesion.
Prognosis Increasing severity in athrosclerosis has been linked with decreasing concentration of hyaluronan distribution. Yet, the role HA may be playing during earlier phases of the disease is yet to be determined due to difficulty in early detection of the disease. Decreased HAS2 activity is stipulated to be playing a possible role in this matter.
  

Bibliography

Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme.
Camenisch TD, Spicer AP, Brehm-Gibson T, Biesterfeldt J, Augustine ML, Calabro A Jr, Kubalak S, Klewer SE, McDonald JA.
J Clin Invest. 2000 Aug;106(3):349-60.
PMID 10930438
 
Regulation of hyaluronan synthase-2 expression in human intestinal mesenchymal cells: mechanisms of interleukin-1beta-mediated induction.
Ducale AE, Ward SI, Dechert T, Yager DR.
Am J Physiol Gastrointest Liver Physiol. 2005 Sep;289(3):G462-70. Epub 2005 Jan 27.
PMID 15677552
 
Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties.
Itano N, Sawai T, Yoshida M, Lenas P, Yamada Y, Imagawa M, Shinomura T, Hamaguchi M, Yoshida Y, Ohnuki Y, Miyauchi S, Spicer AP, McDonald JA, Kimata K.
J Biol Chem. 1999 Aug 27;274(35):25085-92.
PMID 10455188
 
Hyaluronan-cell interactions in cancer and vascular disease.
J Biol Chem. 2002 Feb 15;277(7):4593-6. Epub 2001 Nov 20.
Toole BP, Wight TN, Tammi MI.
PMID 11717318
 
Identification and analysis of the promoter region of the human hyaluronan synthase 2 gene.
Monslow J, Williams JD, Guy CA, Price IK, Craig KJ, Williams HJ, Williams NM, Martin J, Coleman SL, Topley N, Spicer AP, Buckland PR, Davies M, Bowen T.
J Biol Chem. 2004 May 14;279(20):20576-81. Epub 2004 Feb 25.
PMID 14988410
 
Integration of the activation of the human hyaluronan synthase 2 gene promoter by common cofactors of the transcription factors retinoic acid receptor and nuclear factor kappaB.
Saavalainen K, Tammi MI, Bowen T, Schmitz ML, Carlberg C.
J Biol Chem. 2007 Apr 13;282(15):11530-9. Epub 2007 Feb 15.
PMID 17307735
 
Hyaluronan and hyaluronidase in genitourinary tumors.
Simpson MA, Lokeshwar VB.
Front Biosci. 2008 May 1;13:5664-80.
PMID 18508614
 
Three vertebrate hyaluronan synthases are expressed during mouse development in distinct spatial and temporal patterns.
Tien JY, Spicer AP.
Dev Dyn. 2005 May;233(1):130-41.
PMID 15765504
 

Citation

This paper should be referenced as such :
Escudero, D
HAS2 (hyaluronan synthase 2)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(2):121-123.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/HAS2ID412ch8q24.html


Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  Soft Tissues: Lipoblastoma
Soft tissue tumors: an overview


External links

Nomenclature
HGNC (Hugo)HAS2   4819
Cards
AtlasHAS2ID412ch8q24
Entrez_Gene (NCBI)HAS2  3037  hyaluronan synthase 2
Aliases
GeneCards (Weizmann)HAS2
Ensembl hg19 (Hinxton)ENSG00000170961 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000170961 [Gene_View]  chr8:121613031-121641390 [Contig_View]  HAS2 [Vega]
ICGC DataPortalENSG00000170961
TCGA cBioPortalHAS2
AceView (NCBI)HAS2
Genatlas (Paris)HAS2
WikiGenes3037
SOURCE (Princeton)HAS2
Genetics Home Reference (NIH)HAS2
Genomic and cartography
./ex|d%f.html#GOLDP TARGET=Goldenpath>GoldenPath hg38 (UCSC)HAS2  -     chr8:121613031-121641390 -  8q24.13   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)HAS2  -     8q24.13   [Description]    (hg19-Feb_2009)
EnsemblHAS2 - 8q24.13 [CytoView hg19]  HAS2 - 8q24.13 [CytoView hg38]
Mapping of homologs : NCBIHAS2 [Mapview hg19]  HAS2 [Mapview hg38]
OMIM601636   
Gene and transcription
Genbank (Entrez)AJ604570 AK297724 BC069353 BC109071 BC109072
RefSeq transcript (Entrez)NM_005328
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)HAS2
Cluster EST : UnigeneHs.668686 [ NCBI ]
CGAP (NCI)Hs.668686
Alternative Splicing GalleryENSG00000170961
Gene ExpressionHAS2 [ NCBI-GEO ]   HAS2 [ EBI - ARRAY_EXPRESS ]   HAS2 [ SEEK ]   HAS2 [ MEM ]
Gene Expression Viewer (FireBrowse)HAS2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)3037
GTEX Portal (Tissue expression)HAS2
Human Protein AtlasENSG00000170961-HAS2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92819   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ92819  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ92819
Splice isoforms : SwissVarQ92819
Catalytic activity : Enzyme2.4.1.212 [ Enzyme-Expasy ]   2.4.1.2122.4.1.212 [ IntEnz-EBI ]   2.4.1.212 [ BRENDA ]   2.4.1.212 [ KEGG ]   
PhosPhoSitePlusQ92819
Domains : Interpro (EBI)Glyco_trans_2-like    HAS2    Nucleotide-diphossugar_trans   
Domain families : Pfam (Sanger)Glycos_transf_2 (PF00535)   
Domain families : Pfam (NCBI)pfam00535   
Conserved Domain (NCBI)HAS2
DMDM Disease mutations3037
Blocks (Seattle)HAS2
SuperfamilyQ92819
Human Protein Atlas [tissue]ENSG00000170961-HAS2 [tissue]
Peptide AtlasQ92819
HPRD07045
IPIIPI00023713   IPI00908494   
Protein Interaction databases
DIP (DOE-UCLA)Q92819
IntAct (EBI)Q92819
FunCoupENSG00000170961
BioGRIDHAS2
STRING (EMBL)HAS2
ZODIACHAS2
Ontologies - Pathways
QuickGOQ92819
Ontology : AmiGOvasculogenesis  kidney development  cytoplasm  integral component of plasma membrane  positive regulation of cell proliferation  positive regulation of keratinocyte proliferation  positive regulation of smooth muscle cell migration  hyaluronan biosynthetic process  hyaluronan biosynthetic process  hyaluronan biosynthetic process  hyaluronan biosynthetic process  positive regulation of cell migration  positive regulation of urine volume  cellular response to platelet-derived growth factor stimulus  atrioventricular canal development  estrous cycle  extracellular polysaccharide biosynthetic process  extracellular polysaccharide biosynthetic process  hyaluronan synthase activity  hyaluronan synthase activity  positive regulation of keratinocyte migration  bone morphogenesis  renal water absorption  cellular response to interleukin-1  cellular response to tumor necrosis factor  cellular response to fluid shear stress  extracellular matrix assembly  extracellular matrix assembly  endocardial cushion to mesenchymal transition  positive regulation of substrate adhesion-dependent cell spreading  positive regulation of hyaluronan biosynthetic process  positive regulation of monocyte aggregation  
Ontology : EGO-EBIvasculogenesis  kidney development  cytoplasm  integral component of plasma membrane  positive regulation of cell proliferation  positive regulation of keratinocyte proliferation  positive regulation of smooth muscle cell migration  hyaluronan biosynthetic process  hyaluronan biosynthetic process  hyaluronan biosynthetic process  hyaluronan biosynthetic process  positive regulation of cell migration  positive regulation of urine volume  cellular response to platelet-derived growth factor stimulus  atrioventricular canal development  estrous cycle  extracellular polysaccharide biosynthetic process  extracellular polysaccharide biosynthetic process  hyaluronan synthase activity  hyaluronan synthase activity  positive regulation of keratinocyte migration  bone morphogenesis  renal water absorption  cellular response to interleukin-1  cellular response to tumor necrosis factor  cellular response to fluid shear stress  extracellular matrix assembly  extracellular matrix assembly  endocardial cushion to mesenchymal transition  positive regulation of substrate adhesion-dependent cell spreading  positive regulation of hyaluronan biosynthetic process  positive regulation of monocyte aggregation  
REACTOMEQ92819 [protein]
REACTOME PathwaysR-HSA-2142850 [pathway]   
NDEx NetworkHAS2
Atlas of Cancer Signalling NetworkHAS2
Wikipedia pathwaysHAS2
Orthology - Evolution
OrthoDB3037
GeneTree (enSembl)ENSG00000170961
Phylogenetic Trees/Animal Genes : TreeFamHAS2
HOVERGENQ92819
HOGENOMQ92819
Homologs : HomoloGeneHAS2
Homology/Alignments : Family Browser (UCSC)HAS2
Gene fusions - Rearrangements
Fusion : MitelmanHAS2/HHLA1 [8q24.13/8q24.22]  
Fusion : MitelmanHAS2/PLAG1 [8q24.13/8q12.1]  [del(8)(q12q24)]  
Fusion : COSMICHAS2 [8q24.13]  -  PLAG1 [8q12.1]  [fusion_1094]  [fusion_1095]  [fusion_1096]  [fusion_1100]  
Fusion: TCGAHAS2 8q24.13 HHLA1 8q24.22 LUAD
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerHAS2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)HAS2
dbVarHAS2
ClinVarHAS2
1000_GenomesHAS2 
Exome Variant ServerHAS2
ExAC (Exome Aggregation Consortium)ENSG00000170961
GNOMAD BrowserENSG00000170961
Genetic variants : HAPMAP3037
Genomic Variants (DGV)HAS2 [DGVbeta]
DECIPHERHAS2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisHAS2 
Mutations
ICGC Data PortalHAS2 
TCGA Data PortalHAS2 
Broad Tumor PortalHAS2
OASIS PortalHAS2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICHAS2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDHAS2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch HAS2
DgiDB (Drug Gene Interaction Database)HAS2
DoCM (Curated mutations)HAS2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)HAS2 (select a term)
intoGenHAS2
NCG5 (London)HAS2
Cancer3DHAS2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601636   
Orphanet
MedgenHAS2
Genetic Testing Registry HAS2
NextProtQ92819 [Medical]
TSGene3037
GENETestsHAS2
Target ValidationHAS2
Huge Navigator HAS2 [HugePedia]
snp3D : Map Gene to Disease3037
BioCentury BCIQHAS2
ClinGenHAS2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD3037
Chemical/Pharm GKB GenePA29195
Clinical trialHAS2
Miscellaneous
canSAR (ICR)HAS2 (select the gene name)
Probes
Litterature
PubMed77 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineHAS2
EVEXHAS2
GoPubMedHAS2
iHOPHAS2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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