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HYAL2 (Hyaluronoglucosaminidase 2)

Written2007-11Lillian SN Chow, Kwok-Wai Lo
Department of Anatomical, Cellular Pathology, State Key Laboratory of Oncology,, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)LuCa-2
LUCA2
Other alias
HGNC (Hugo) HYAL2
LocusID (NCBI) 8692
Atlas_Id 40904
Location 3p21.31  [Link to chromosome band 3p21]
Location_base_pair Starts at 50317790 and ends at 50322850 bp from pter ( according to hg19-Feb_2009)  [Mapping HYAL2.png]
Local_order Telomeric to TUSC2 and centromeric to HAYL1.
Fusion genes
(updated 2016)
HYAL2 (3p21.31) / HYAL2 (3p21.31)IGFBP7 (4q12) / HYAL2 (3p21.31)
Note HYAL2 was identified in an EST database search of PH-20 hyaluronidase related sequences. HYAL2 appears to be an inactive hyaluronidase. Characterization of HYAL2 mostly focuses on its role as the cell entry receptor of Jaagsiekte sheep retrovirus (JSRV), and the putative function as a tumor suppressor gene, based on its specific chromosomal location.

DNA/RNA

 
  Two alternatively spliced variants (NM_033158.2 and NM_003773.2) of HYAL2 are shown. Both of them contain four exons. Black boxes represent the coding exons of HYAL2. White boxes represent untranslated regions.
Description The HYAL2 gene contains 4 exons, spanning 4.99 kb.
Transcription The gene encodes two alternatively spliced transcripts (NM_033158 and NM_003773) which differ only in the 5' UTR. Distinct noncoding exon 1 was found in these two transcripts. Both variants encode the same protein. The ORF size is 1422 bp.
Pseudogene No known pseudogenes.

Protein

 
  The HYAL2 protein contains a N-terminal signal peptide (1-20) and a epidermal growth factor (EGF)-like domain (365-469).
Description The 473 amino-acid peptide encodes the HYAL2 protein with a predicted molecular weight of 53.9 KDa. The protein is comprised of a N-terminal signal peptide (amino acids 1-20) and a epidermal growth factor ( EGF )-like domain at amino acids 365-469 (by SMART prediction).
Expression High level of HYAL2 expression was detected in most tissues, including liver, kidney, lung and heart. Expression was low or absent in brain.
Localisation Originally shown to be lysosomal but subsequently proved to be a glycosylphosphatidylinositol (GPI)-anchored cell surface protein.
Function Hyaluronidases degrade hyaluronan, one of the major glycosaminoglycans of the extracellular matrix (ECM). The level of hyaluronan is regulated by a balance between hyaluronan synthase and HYAL enzyme activities. Hyaluronan is suggested to be involved in embryonic development, cell proliferation, migration and wound healing. Although originally supposed to be active at pH 4.0, HYAL2 actually displayed minimal to undetectable hyaluronidase activity in subsequent studies. The hyaluronidase activity of HYAL2 remains controversial.
Homology HYAL2 belongs to a family of hyaluronoglucosaminidases. Other members include HYAL1, HYAL3, HYAL4 and Spam1.

Mutations

Note No germline or somatic mutation is reported.

Implicated in

Note
  
Entity Possible in lung cancer and breast cancer.
Note HYAL2 is located within a 120-kb minimal deletion region at 3p21.3. a chromosomal segment known to harbor multiple candidate tumor suppressor genes in breast and lung cancers. Nevertheless, HYAL2 does not possess tumor suppressor function, as evident by in vitro and in vivo studies in lung cancer models.
HYAL2 serves as the cellular receptor that mediates entry of the Jaagsiekte sheep retrovirus (JSRV), and its receptor function is independent on its catalytic activity. The JSRV envelope (Env) protein is believed to be the active oncogene. The viral Env transforms epithelial cells through activation of RON receptor tyrosine kinase, also called macrophage stimulating-1 receptor ( MST1R ), and followed by activating PI3K/Akt signaling cascade and MAPK signaling cascade. HYAL2 physically interacts and negatively regulates RON.
JSRV infects the epithelial cells of the lower airway of sheep and goats, resulting in ovine pulmonary adenocarinoma, sharing features with human bronchioloalveolar carcinoma. Danilkovitch-Miagkova et al. (2003) demonstrated activated RON in a subset of human bronchioloalveolar carcinoma tumors, suggesting RON involvement in this type of human lung cancer.
Disease Lung cancer; bronchioloalveolar carcinoma; non-Hodgkin lymphoma ; breast cancer.
Prognosis Increased level of HYAL2 deletions in sputum of Stage I non-small-cell lung cancer patients was associated with pack-years of smoking, but independent on patients' age, gender, histologic tumor type and tumor size and location. HYAL2 mRNA expression was inversely correlated with lymphoma aggressiveness.
Oncogenesis HYAL2 mRNA expression was lost in lung cancer cell lines. However, expression of HYAL2 was retained in esophageal squamous carcinoma and nasopharyngeal carcinoma cell lines. Highly invasive breast cancer cell lines preferentially express HYAL2.
Systemic administration of protamine-complexed vectors expressing HYAL2 inhibited lung metastatic foci in nu/nu mice. Intratumoral injection of same construct failed to suppress primary tumor growth or induce apoptosis, suggesting HYAL2 may function at the level of metastasis.
  

Bibliography

Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness.
Bertrand P, Courel MN, Maingonnat C, Jardin F, Tilly H, Bastard C
International journal of cancer. Journal international du cancer. 2005 ; 113 (2) : 207-212.
PMID 15386412
 
RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma.
Chow LS, Lo KW, Kwong J, To KF, Tsang KS, Lam CW, Dammann R, Huang DP
International journal of cancer. Journal international du cancer. 2004 ; 109 (6) : 839-847.
PMID 15027117
 
Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.
Danilkovitch-Miagkova A, Duh FM, Kuzmin I, Angeloni D, Liu SL, Miller AD, Lerman MI
Proceedings of the National Academy of Sciences of the United States of America. 2003 ; 100 (8) : 4580-4585.
PMID 12676986
 
Expression of several genes in the human chromosome 3p21.3 homozygous deletion region by an adenovirus vector results in tumor suppressor activities in vitro and in vivo.
Ji L, Nishizaki M, Gao B, Burbee D, Kondo M, Kamibayashi C, Xu K, Yen N, Atkinson EN, Fang B, Lerman MI, Roth JA, Minna JD
Cancer research. 2002 ; 62 (9) : 2715-2720.
PMID 11980673
 
HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.
Lepperdinger G, Strobl B, Kreil G
The Journal of biological chemistry. 1998 ; 273 (35) : 22466-22470.
PMID 9712871
 
Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer.
Li R, Todd NW, Qiu Q, Fan T, Zhao RY, Rodgers WH, Fang HB, Katz RL, Stass SA, Jiang F
Clinical cancer research : an official journal of the American Association for Cancer Research. 2007 ; 13 (2 Pt 1) : 482-487.
PMID 17255269
 
Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation.
Rai SK, Duh FM, Vigdorovich V, Danilkovitch-Miagkova A, Lerman MI, Miller AD
Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (8) : 4443-4448.
PMID 11296287
 
Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene.
Sekido Y, Ahmadian M, Wistuba II, Latif F, Bader S, Wei MH, Duh FM, Gazdar AF, Lerman MI, Minna JD
Oncogene. 1998 ; 16 (24) : 3151-3157.
PMID 9671394
 
The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer.
Udabage L, Brownlee GR, Nilsson SK, Brown TJ
Experimental cell research. 2005 ; 310 (1) : 205-217.
PMID 16125700
 
Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus.
Vigdorovich V, Miller AD, Strong RK
Journal of virology. 2007 ; 81 (7) : 3124-3129.
PMID 17229709
 

Citation

This paper should be referenced as such :
Chow, LSN ; Lo, KW
HYAL2 (hyaluronoglucosaminidase 2)
Atlas Genet Cytogenet Oncol Haematol. 2008;12(4):279-281.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/HYAL2ID40904ch3p21.html


External links

Nomenclature
HGNC (Hugo)HYAL2   5321
Cards
AtlasHYAL2ID40904ch3p21
Entrez_Gene (NCBI)HYAL2  8692  hyaluronoglucosaminidase 2
AliasesLUCA2
GeneCards (Weizmann)HYAL2
Ensembl hg19 (Hinxton)ENSG00000068001 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000068001 [Gene_View]  chr3:50317790-50322850 [Contig_View]  HYAL2 [Vega]
ICGC DataPortalENSG00000068001
TCGA cBioPortalHYAL2
AceView (NCBI)HYAL2
Genatlas (Paris)HYAL2
WikiGenes8692
SOURCE (Princeton)HYAL2
Genetics Home Reference (NIH)HYAL2
Genomic and cartography
GoldenPath hg38 (UCSC)HYAL2  -     chr3:50317790-50322850 -  3p21.31   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)HYAL2  -     3p21.31   [Description]    (hg19-Feb_2009)
EnsemblHYAL2 - 3p21.31 [CytoView hg19]  HYAL2 - 3p21.31 [CytoView hg38]
Mapping of homologs : NCBIHYAL2 [Mapview hg19]  HYAL2 [Mapview hg38]
OMIM603551   
Gene and transcription
Genbank (Entrez)AF070608 AJ000099 AJ844619 AJ844620 AK092449
RefSeq transcript (Entrez)NM_003773 NM_033158
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)HYAL2
Cluster EST : UnigeneHs.76873 [ NCBI ]
CGAP (NCI)Hs.76873
Alternative Splicing GalleryENSG00000068001
Gene ExpressionHYAL2 [ NCBI-GEO ]   HYAL2 [ EBI - ARRAY_EXPRESS ]   HYAL2 [ SEEK ]   HYAL2 [ MEM ]
Gene Expression Viewer (FireBrowse)HYAL2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)8692
GTEX Portal (Tissue expression)HYAL2
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ12891   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ12891  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ12891
Splice isoforms : SwissVarQ12891
Catalytic activity : Enzyme3.2.1.35 [ Enzyme-Expasy ]   3.2.1.353.2.1.35 [ IntEnz-EBI ]   3.2.1.35 [ BRENDA ]   3.2.1.35 [ KEGG ]   
PhosPhoSitePlusQ12891
Domaine pattern : Prosite (Expaxy)EGF_1 (PS00022)    EGF_2 (PS01186)   
Domains : Interpro (EBI)Aldolase_TIM    Glycoside_hydrolase_SF    Hyaluronidase   
Domain families : Pfam (Sanger)Glyco_hydro_56 (PF01630)   
Domain families : Pfam (NCBI)pfam01630   
Conserved Domain (NCBI)HYAL2
DMDM Disease mutations8692
Blocks (Seattle)HYAL2
SuperfamilyQ12891
Human Protein AtlasENSG00000068001
Peptide AtlasQ12891
HPRD04649
IPIIPI00021531   IPI00925550   IPI00925328   IPI00925145   IPI00924943   IPI00924743   
Protein Interaction databases
DIP (DOE-UCLA)Q12891
IntAct (EBI)Q12891
FunCoupENSG00000068001
BioGRIDHYAL2
STRING (EMBL)HYAL2
ZODIACHYAL2
Ontologies - Pathways
QuickGOQ12891
Ontology : AmiGOGolgi membrane  response to reactive oxygen species  RNA polymerase II transcription coactivator activity  virus receptor activity  kidney development  hematopoietic progenitor cell differentiation  hyalurononglucosaminidase activity  hyalurononglucosaminidase activity  hyalurononglucosaminidase activity  protein binding  hyaluronic acid binding  cytoplasm  lysosome  endoplasmic reticulum  cytosol  plasma membrane  microvillus  carbohydrate metabolic process  glycosaminoglycan catabolic process  response to virus  cell surface  cell surface  multicellular organism aging  negative regulation of fibroblast migration  apical plasma membrane  fusion of virus membrane with host plasma membrane  transformation of host cell by virus  transformation of host cell by virus  enzyme binding  endocytic vesicle  hyaluronan catabolic process  hyaluronan catabolic process  receptor signaling protein tyrosine kinase inhibitor activity  negative regulation of cell growth  receptor tyrosine kinase binding  anchored component of external side of plasma membrane  anchored component of external side of plasma membrane  cytoplasmic vesicle  hyaluronoglucuronidase activity  positive regulation of urine volume  monocyte activation  positive regulation of protein import into nucleus  negative regulation of MAP kinase activity  cellular response to fibroblast growth factor stimulus  membrane raft  positive regulation of transcription from RNA polymerase II promoter  anchored component of plasma membrane  response to antibiotic  viral entry into host cell  perinuclear region of cytoplasm  skeletal system morphogenesis  transforming growth factor beta binding  positive regulation of inflammatory response  cartilage development  defense response to virus  negative regulation of protein kinase B signaling  multicellular organismal iron ion homeostasis  negative regulation of protein tyrosine kinase activity  renal water absorption  cellular response to interleukin-1  cellular response to tumor necrosis factor  cellular response to UV-B  cellular response to transforming growth factor beta stimulus  RNA polymerase II transcription factor complex  positive regulation of interleukin-8 secretion  positive regulation of interleukin-6 secretion  positive regulation of extrinsic apoptotic signaling pathway  
Ontology : EGO-EBIGolgi membrane  response to reactive oxygen species  RNA polymerase II transcription coactivator activity  virus receptor activity  kidney development  hematopoietic progenitor cell differentiation  hyalurononglucosaminidase activity  hyalurononglucosaminidase activity  hyalurononglucosaminidase activity  protein binding  hyaluronic acid binding  cytoplasm  lysosome  endoplasmic reticulum  cytosol  plasma membrane  microvillus  carbohydrate metabolic process  glycosaminoglycan catabolic process  response to virus  cell surface  cell surface  multicellular organism aging  negative regulation of fibroblast migration  apical plasma membrane  fusion of virus membrane with host plasma membrane  transformation of host cell by virus  transformation of host cell by virus  enzyme binding  endocytic vesicle  hyaluronan catabolic process  hyaluronan catabolic process  receptor signaling protein tyrosine kinase inhibitor activity  negative regulation of cell growth  receptor tyrosine kinase binding  anchored component of external side of plasma membrane  anchored component of external side of plasma membrane  cytoplasmic vesicle  hyaluronoglucuronidase activity  positive regulation of urine volume  monocyte activation  positive regulation of protein import into nucleus  negative regulation of MAP kinase activity  cellular response to fibroblast growth factor stimulus  membrane raft  positive regulation of transcription from RNA polymerase II promoter  anchored component of plasma membrane  response to antibiotic  viral entry into host cell  perinuclear region of cytoplasm  skeletal system morphogenesis  transforming growth factor beta binding  positive regulation of inflammatory response  cartilage development  defense response to virus  negative regulation of protein kinase B signaling  multicellular organismal iron ion homeostasis  negative regulation of protein tyrosine kinase activity  renal water absorption  cellular response to interleukin-1  cellular response to tumor necrosis factor  cellular response to UV-B  cellular response to transforming growth factor beta stimulus  RNA polymerase II transcription factor complex  positive regulation of interleukin-8 secretion  positive regulation of interleukin-6 secretion  positive regulation of extrinsic apoptotic signaling pathway  
Pathways : KEGGGlycosaminoglycan degradation   
REACTOMEQ12891 [protein]
REACTOME PathwaysR-HSA-2160916 [pathway]   
NDEx NetworkHYAL2
Atlas of Cancer Signalling NetworkHYAL2
Wikipedia pathwaysHYAL2
Orthology - Evolution
OrthoDB8692
GeneTree (enSembl)ENSG00000068001
Phylogenetic Trees/Animal Genes : TreeFamHYAL2
HOVERGENQ12891
HOGENOMQ12891
Homologs : HomoloGeneHYAL2
Homology/Alignments : Family Browser (UCSC)HYAL2
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerHYAL2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)HYAL2
dbVarHYAL2
ClinVarHYAL2
1000_GenomesHYAL2 
Exome Variant ServerHYAL2
ExAC (Exome Aggregation Consortium)HYAL2 (select the gene name)
Genetic variants : HAPMAP8692
Genomic Variants (DGV)HYAL2 [DGVbeta]
DECIPHERHYAL2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisHYAL2 
Mutations
ICGC Data PortalHYAL2 
TCGA Data PortalHYAL2 
Broad Tumor PortalHYAL2
OASIS PortalHYAL2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICHYAL2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDHYAL2
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 HYAL2
DgiDB (Drug Gene Interaction Database)HYAL2
DoCM (Curated mutations)HYAL2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)HYAL2 (select a term)
intoGenHYAL2
NCG5 (London)HYAL2
Cancer3DHYAL2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM603551   
Orphanet
MedgenHYAL2
Genetic Testing Registry HYAL2
NextProtQ12891 [Medical]
TSGene8692
GENETestsHYAL2
Target ValidationHYAL2
Huge Navigator HYAL2 [HugePedia]
snp3D : Map Gene to Disease8692
BioCentury BCIQHYAL2
ClinGenHYAL2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD8692
Chemical/Pharm GKB GenePA29572
Clinical trialHYAL2
Miscellaneous
canSAR (ICR)HYAL2 (select the gene name)
Probes
Litterature
PubMed54 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineHYAL2
EVEXHYAL2
GoPubMedHYAL2
iHOPHYAL2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Wed Jun 7 12:04:57 CEST 2017

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