HYAL2 (Hyaluronoglucosaminidase 2)

2007-11-01 Lillian SN Chow , Kwok-Wai Lo Affiliation

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

Identity

HGNC

HYAL2

LOCATION

3p21.31

LOCUSID

8692

ALIAS

LUCA2

FUSION GENES

Show Gene Fusions

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.

Proteins

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

Entity name

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

Pubmed ID	Last Year	Title	Authors
15386412	2005	Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness.	Bertrand P et al
15027117	2004	RASSF1A is a target tumor suppressor from 3p21.3 in nasopharyngeal carcinoma.	Chow LS et al
12676986	2003	Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.	Danilkovitch-Miagkova A et al
11980673	2002	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 et al
9712871	1998	HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity.	Lepperdinger G et al
17255269	2007	Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer.	Li R et al
11296287	2001	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 et al
9671394	1998	Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene.	Sekido Y et al
16125700	2005	The over-expression of HAS2, Hyal-2 and CD44 is implicated in the invasiveness of breast cancer.	Udabage L et al
17229709	2007	Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus.	Vigdorovich V et al

Other Information

Locus ID:

NCBI: 8692
MIM: 603551
HGNC: 5321
Ensembl: ENSG00000068001

Variants:

dbSNP: 8692
ClinVar: 8692
TCGA: ENSG00000068001
COSMIC: HYAL2

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000068001	ENST00000357750	Q12891
ENSG00000068001	ENST00000395139	Q12891
ENSG00000068001	ENST00000415028	C9J700
ENSG00000068001	ENST00000424190	C9JBF5
ENSG00000068001	ENST00000426286	C9JSD1
ENSG00000068001	ENST00000428028	C9JSI7
ENSG00000068001	ENST00000442581	Q12891
ENSG00000068001	ENST00000447092	Q12891
ENSG00000068001	ENST00000458018	C9K016

Expression (GTEx)

100

150

200

250

300

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Glycosaminoglycan degradation	KEGG	ko00531
Glycosaminoglycan degradation	KEGG	hsa00531
Metabolic pathways	KEGG	hsa01100
Dermatan sulfate degradation	KEGG	hsa_M00076
Chondroitin sulfate degradation	KEGG	hsa_M00077
Dermatan sulfate degradation	KEGG	M00076
Chondroitin sulfate degradation	KEGG	M00077
Metabolism	REACTOME	R-HSA-1430728
Metabolism of carbohydrates	REACTOME	R-HSA-71387
Glycosaminoglycan metabolism	REACTOME	R-HSA-1630316
Hyaluronan metabolism	REACTOME	R-HSA-2142845
Hyaluronan uptake and degradation	REACTOME	R-HSA-2160916

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
19443707	2009	Platelet-derived hyaluronidase 2 cleaves hyaluronan into fragments that trigger monocyte-mediated production of proinflammatory cytokines.	48
20554532	2010	Reactive oxygen species and hyaluronidase 2 regulate airway epithelial hyaluronan fragmentation.	40
12676986	2003	Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus.	36
12584308	2003	Role of virus receptor Hyal2 in oncogenic transformation of rodent fibroblasts by sheep betaretrovirus env proteins.	35
20864512	2010	A panel of sputum-based genomic marker for early detection of lung cancer.	26
25411425	2015	Platelet hyaluronidase-2: an enzyme that translocates to the surface upon activation to function in extracellular matrix degradation.	22
19435493	2009	Expression of hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) in serous ovarian carcinomas: inverse correlation between HYAL1 and hyaluronan content.	20
15596803	2005	Expression and characterization of a soluble, active form of the jaagsiekte sheep retrovirus receptor, Hyal2.	17
16837837	2006	Hyaluronan expression following middle cerebral artery occlusion in the rat.	17
12174938	2002	Hyaluronidase is more elevated in human brain metastases than in primary brain tumours.	15

Citation

Lillian SN Chow ; Kwok-Wai Lo

HYAL2 (Hyaluronoglucosaminidase 2)

Atlas Genet Cytogenet Oncol Haematol. 2007-11-01

Online version: http://atlasgeneticsoncology.org/gene/40904/hyal2