Alternative titles; symbols
HGNC Approved Gene Symbol: HYAL2
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:50,317,808-50,322,745 (from NCBI)
Hyaluronidases degrade hyaluronic acid (HA), a glycosaminoglycan present in the extracellular matrix of vertebrates. Hyaluronidase-2 exhibits very low hyaluronidase activity (Lepperdinger et al., 1998; Rai et al., 2001).
By searching an EST database for sequences related to the PH-20 (600930) hyaluronidase, Lepperdinger et al. (1998) identified HYAL2 cDNAs. The HYAL2 cDNAs encode a preprotein with an N-terminal signal peptide. The predicted 452-amino acid mature protein is 36.5% identical to PH-20. Northern blot analysis indicated that HYAL2 was expressed in all human tissues tested except adult brain, and Western blot analysis detected Hyal2 protein in all mouse tissues examined except adult brain.
Strobl et al. (1998) characterized Hyal2, the mouse homolog of HYAL2. The deduced proteins are 82% identical.
Lepperdinger et al. (1998) found that, unlike HYAL1 (607071), whose properties suggested that it was membrane associated, a fusion protein of HYAL2 and green fluorescent protein (GFP) localized to lysosomes of mammalian cells. HYAL2 hyaluronidase activity had a pH optimum below 4. Also in contrast to HYAL1, the HYAL2 enzyme hydrolyzed only HA of high molecular mass, yielding intermediate-sized HA fragments of approximately 20 kD, which were further hydrolyzed to small oligosaccharides by PH-20. The authors noted that the intermediate-sized HA fragments have specific biologic functions. Lepperdinger et al. (1998) concluded that HYAL2 encodes a lysosomal hyaluronidase that is present in many cell types.
Rai et al. (2001) and Dirks et al. (2002) showed that HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored protein on the cell surface and serves as a receptor for entry into the cell of the jaagsiekte sheep retrovirus (JSRV). In sheep, JSRV causes a contagious form of lung cancer that arises from epithelial cells in the lower airway, including type II aveolar and bronchiolar epithelial cells. De las Heras et al. (2000) reported that antiserum directed against the JSRV capsid protein crossreacted with 30% of human pulmonary adenocarcinoma samples but not with normal lung tissue or adenocarcinomas from other tissues. These findings supported the possibility of a viral etiology of some human lung cancers, particularly the bronchioloalveolar adenocarcinoma type, which is morphologically very similar to the sheep tumors. The viral envelope (Env) protein alone can transform cultured cells, and Danilkovitch-Miagkova et al. (2003) hypothesized that Env could bind and sequester the HYAL2 receptor and thus liberate a potential oncogenic factor bound and negatively controlled by HYAL2. They showed that the HYAL2 receptor protein is associated with the RON receptor tyrosine kinase, also called macrophage stimulating-1 receptor (MST1R; 600168), rendering it functionally silent. In human cells expressing a JSRV Env transgene, the Env protein physically associated with HYAL2. RON liberated from the association with HYAL2 becomes functionally active and consequently activates the AKT1 (164730) and mitogen-activated protein kinase-1 (MAPK1; 176948) pathways, leading to oncogenic transformation of immortalized human bronchial epithelial cells. 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.
Miller (2002) provided an explanation for the discrepancy between the conclusions of Lepperdinger et al. (1998) and Rai et al. (2001), the former that HYAL2 is a lysosomal enzyme and the latter that it is a cell surface enzyme. Lepperdinger et al. (1998) linked GFP to the carboxy end of HYAL2 and found GFP in the lysosome, leading to the conclusion that HYAL2 is also in the lysosome. The findings of Rai et al. (2001) that HYAL2 is a GPI-anchored protein on the cell surface showed that GFP would likely be cleaved from HYAL2 during GPI addition, leaving HYAL2 on the cell surface and resulting in GFP transit to the lysosome for degradation. Rai et al. (2001) also showed that HYAL2 has very low hyaluronidase activity, if any, compared to serum hyaluronidase HYAL1, and that HYAL2 serves as a receptor for JSRV.
Using hyaluronan as substrate, Vigdorovich et al. (2007) demonstrated that recombinant soluble HYAL2 had hyaluronidase activity, with a sharp pH optimum of 5.6. Mutation analysis showed that hyaluronidase activity was not required for HYAL2 to function as JSRV receptor.
Strobl et al. (1998) found that the human and mouse HYAL2 genes contain 4 exons and have the same exon-intron organization.
Lepperdinger et al. (1998) stated that the HYAL2 gene is identical to LUCA2, which Wei et al. (1996) positioned on a contig of human chromosome 3p21.3, a region frequently deleted in lung cancer (see 182280). Wei et al. (1996) observed that LUCA2 is located near LUCA1 (HYAL1; 607071). By analysis of an interspecific backcross, Strobl et al. (1998) mapped the Hyal2 gene to mouse chromosome 9 in a region showing homology of synteny with human 3p21.
Jaagsiekte sheep retrovirus (JSRV) causes a contagious lung cancer in sheep and goats, with significant animal health and economic consequences. The host range of JSRV is in part limited by species-specific differences in the virus entry receptor, hyaluronidase-2 (Hyal2), which is not functional as a receptor in mice but is functional in humans. Sheep are immunotolerant of JSRV because of expression of closely related endogenous retroviruses, which are not present in humans and most other species, and that may facilitate oncogenesis. Using a replication-incompetent adeno-associated virus vector, Wootton et al. (2005) showed that expression of the JSRV envelope (Env) protein alone in lungs of mice results in tumors with a bronchioloalveolar localization like those seen in sheep. Whereas lethal disease was observed in immunodeficient mice, tumor development was almost entirely blocked in immunocompetent mice. Wootton et al. (2005) concluded that their results provided a rare example of an oncogenic viral structural protein, showed that interaction of the viral Env protein with the virus entry receptor Hyal2 is not required for tumorigenesis, and indicated that immune recognition of Env can protect against JSRV tumorigenesis.
The naked mole rat (Heterocephalus glaber) displays exceptional longevity, with a maximum life span exceeding 30 years. In addition, it is unusually resistant to cancer. Tian et al. (2013) identified a mechanism responsible for the cancer resistance. Tian et al. (2013) found that naked mole rat fibroblasts secrete extremely high molecular mass hyaluronan (HA), which is over 5 times larger than human or mouse HA. This high molecular mass HA accumulates abundantly in naked mole rat tissues owing to the decreased activity of HA-degrading enzymes and a species-specific sequence of hyaluronan synthase-2 (HAS2; 601636). Furthermore, the naked mole rat cells are more sensitive to HA signaling, as they have a higher affinity to HA compared to mouse or human cells. Perturbation of the signaling pathways sufficient for malignant transformation of mouse fibroblasts failed to transform naked mole rat cells. However, once high molecular mass HA was removed by either knocking down HAS2 or overexpressing the HA-degrading enzyme HYAL2, naked mole rat cells became susceptible to malignant transformation and readily formed tumors in mice. Tian et al. (2013) speculated that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels and that this trait may have then been coopted to provide cancer resistance and longevity to this species.
Danilkovitch-Miagkova, A., Duh, F.-M., Kuzmin, I., Angeloni, D., Liu, S.-L., Miller, A. D., Lerman, M. I. Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Proc. Nat. Acad. Sci. 100: 4580-4585, 2003. [PubMed: 12676986] [Full Text: https://doi.org/10.1073/pnas.0837136100]
De las Heras, M., Barsky, S. H., Hasleton, P., Wagner, M., Larson, E., Egan, J., Ortin, A., Gimenez-Mas, J. A., Palmarini, M., Sharp, J. M. Evidence for a protein related immunologically to the jaagsiekte sheep retrovirus in some human lung tumours. Europ. Resp. J. 15: 330-332, 2000.
Dirks, C., Duh, F.-M., Rai, S. K., Lerman, M. I., Miller, A. D. Mechanism of cell entry and transformation by enzootic nasal tumor virus. J. Virol. 76: 2141-2149, 2002. [PubMed: 11836391] [Full Text: https://doi.org/10.1128/jvi.76.5.2141-2149.2002]
Lepperdinger, G., Strobl, B., Kreil, G. HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. J. Biol. Chem. 273: 22466-22470, 1998. [PubMed: 9712871] [Full Text: https://doi.org/10.1074/jbc.273.35.22466]
Miller, A. D. Personal Communication. Seattle, Wash. 12/10/2002.
Rai, S. K., Duh, F.-M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M. I., Miller, A. D. Candidate tumor suppressor HYAL2 is a glycosylphosphatidylinositol (GPI)-anchored cell-surface receptor for jaagsiekte sheep retrovirus, the envelope protein of which mediates oncogenic transformation. Proc. Nat. Acad. Sci. 98: 4443-4448, 2001. [PubMed: 11296287] [Full Text: https://doi.org/10.1073/pnas.071572898]
Strobl, B., Wechselberger, C., Beier, D. R., Lepperdinger, G. Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase. Genomics 53: 214-219, 1998. [PubMed: 9790770] [Full Text: https://doi.org/10.1006/geno.1998.5472]
Tian, X., Azpurua, J., Hine, C., Vaidya, A., Myakishev-Rempel, M., Ablaeva, J., Mao, Z., Nevo, E., Gorbunova, V., Seluanov, A. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature 499: 346-349, 2013. [PubMed: 23783513] [Full Text: https://doi.org/10.1038/nature12234]
Vigdorovich, V., Miller, A. D., Strong, R. K. Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus. J. Virol. 81: 3124-3129, 2007. [PubMed: 17229709] [Full Text: https://doi.org/10.1128/JVI.02177-06]
Wei, M.-H., Latif, F., Bader, S., Kashuba, V., Chen, J.-Y., Duh, F.-M., Sekido, Y., Lee, C.-C., Geil, L., Kuzmin, I., Zabarovsky, E., Klein, G., Zbar, B., Minna, J. D., Lerman, M. I. Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG. Cancer Res. 56: 1487-1492, 1996. [PubMed: 8603390]
Wootton, S. K., Halbert, C. L., Miller, A. D. Sheep retrovirus structural protein induces lung tumours. Nature 434: 904-907, 2005. [PubMed: 15829964] [Full Text: https://doi.org/10.1038/nature03492]