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Gene Review

HYAL2  -  hyaluronoglucosaminidase 2

Homo sapiens

Synonyms: Hyal-2, Hyaluronidase-2, Hyaluronoglucosaminidase-2, LUCA2, LuCa-2, ...
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Disease relevance of HYAL2


High impact information on HYAL2

  • Furthermore, we could not detect hyaluronidase activity associated with or secreted by cells expressing HYAL2, whereas we could easily detect such activity from cells expressing the related serum hyaluronidase HYAL1 [2].
  • Although the function of HYAL2 is currently unknown, other GPI-anchored proteins are involved in signal transduction, and some mediate mitogenic responses, suggesting a potential role of HYAL2 in JSRV Env-mediated oncogenesis [2].
  • These genes, HYAL1 and HYAL2, encode two distinct lysosomal hyaluronidases with different substrate specificities [6].
  • Three immunoglobulin G1 monoclonal antibodies, LuCa2, LuCa3, and LuCa4, were produced by fusing murine myeloma NS1 cells with splenocytes obtained from a BALB/c mouse immunized with SK-MES1 cells derived from human squamous cell carcinoma of the lung [7].
  • LuCa2 antibody was reactive with lung squamous carcinoma and adenocarcinoma tumor tissues and pleural effusions, but only infrequently with those of small cell carcinoma [7].

Chemical compound and disease context of HYAL2

  • This leads to Hyal-2-mediated HA catabolism, HA modification, and cysteine proteinase (cathepsin B) activation resulting in breast tumor cell invasion [8].

Biological context of HYAL2

  • Approximately 4000 bp of 5' flanking sequence of the HYAL-2 gene was characterized [9].
  • The presence of multiple transcriptional initiation sites is a typical feature of TATA-less promoter regions, such as those of HYAL-2 [9].
  • To determine whether the expression of lysosomal hyaluronidases contributes to this regulation, the promoter elements associated with HYAL-2 gene expression were characterized [9].
  • Transient transfection of C-28/I2 cells with various 5' deletion constructs indicated that the region between +959 to +1158 (within intron 1) contains the basal promoter for HYAL-2 in chondrocytes [9].
  • Hyal2 is located in a region of human chromosome 3p21.3 that is often deleted in lung cancer, suggesting that it may be a tumor suppressor [10].

Anatomical context of HYAL2

  • Expression of this cDNA yielded a polypeptide termed HYAL2, which is located in lysosomes [11].
  • RESULTS: PDL fibroblasts expressed HYAL1 and HYAL2 mRNAs, but not PH-20 mRNA [12].
  • Treatment of human articular chondrocytes or C-28/I2 cells with various catabolic cytokines did not alter HYAL-2 mRNA expression, luciferase promoter expression, or hyaluronidase enzymatic activity [9].
  • In addition, HYAL2 and FHIT deletions in sputum were associated with smoking history of cancer patients and smokers (both P < 0.05) [13].
  • We performed entry and interference assays using retroviral vectors pseudotyped with either the JSRV or the ENTV Env and sheep choroid plexus cells, choroid plexus cells stably expressing the JSRV Env protein, human 293T cells, mouse NIH 3T3 cells, or NIH 3T3 cells expressing human hyaluronidase 2 (HYAL2), the cellular receptor for JSRV [14].

Associations of HYAL2 with chemical compounds

  • One of the mechanisms of JSRV-induced cell transformation that has been proposed for epithelial cells involves JSRV Env binding Hyaluronidase 2 (the JSRV receptor), thereby inducing its degradation and allowing the release and activation of RON tyrosine kinase which is normally suppressed by HYAL-2 [15].
  • While generating the Hyal2 mutant, we discovered that our previous analysis of the hyaluronidase activity of Hyal2 was affected by a contaminating hyaluronan lyase, which we have identified as the occlusion-derived baculovirus E66 protein of the recombinant baculovirus used to produce Hyal2 [16].

Other interactions of HYAL2

  • The human HYAL2 gene encodes a lysosomal hyaluronidase that is related to the testicular PH-20 hyaluronidase [17].
  • Further, the hyaluronidase activity reported for human Hyal2, combined with its broad expression pattern, may point to a critical function of Hyal2 in the turnover of hyaluronan, a major extracellular matrix component [3].
  • RESULTS: HYAL2 and FHIT were deleted in 84% and 79% tumors and in 45% and 40% paired sputum, respectively [13].
  • The expression of hyaluronan synthase 2 (HAS2) and hyaluronidase 2 (HYAL2) was analysed in lung tissue [18].
  • In this study, we report that HYAL-2 and RON are not critical for the JSRV Env-induced transformation of the rat epithelial cell line IEC-18, while the cytoplasmic tail of the JSRV Env is critical to transform this cell line [15].

Analytical, diagnostic and therapeutic context of HYAL2

  • Real-time RT-PCR was performed to evaluate HYAL2 mRNA [19].
  • Real-time PCR analysis showed that HAS 2 and HYAL 2 were expressed at significant levels in all specimens [20].


  1. Hyaluronidase 2 negatively regulates RON receptor tyrosine kinase and mediates transformation of epithelial cells by jaagsiekte sheep retrovirus. Danilkovitch-Miagkova, A., Duh, F.M., Kuzmin, I., Angeloni, D., Liu, S.L., Miller, A.D., Lerman, M.I. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. 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, S.K., Duh, F.M., Vigdorovich, V., Danilkovitch-Miagkova, A., Lerman, M.I., Miller, A.D. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  3. Expression and characterization of a soluble, active form of the jaagsiekte sheep retrovirus receptor, Hyal2. Vigdorovich, V., Strong, R.K., Miller, A.D. J. Virol. (2005) [Pubmed]
  4. Hyaluronidase gene profiling and role of hyal-1 overexpression in an orthotopic model of prostate cancer. Patel, S., Turner, P.R., Stubberfield, C., Barry, E., Rohlff, C.R., Stamps, A., McKenzie, E., Young, K., Tyson, K., Terrett, J., Box, G., Eccles, S., Page, M.J. Int. J. Cancer (2002) [Pubmed]
  5. Gene transfer to respiratory epithelia with lentivirus pseudotyped with Jaagsiekte sheep retrovirus envelope glycoprotein. Sinn, P.L., Penisten, A.K., Burnight, E.R., Hickey, M.A., Williams, G., McCoy, D.M., Mallampalli, R.K., McCray, P.B. Hum. Gene Ther. (2005) [Pubmed]
  6. Mutations in HYAL1, a member of a tandemly distributed multigene family encoding disparate hyaluronidase activities, cause a newly described lysosomal disorder, mucopolysaccharidosis IX. Triggs-Raine, B., Salo, T.J., Zhang, H., Wicklow, B.A., Natowicz, M.R. Proc. Natl. Acad. Sci. U.S.A. (1999) [Pubmed]
  7. Monoclonal antibodies to human squamous cell carcinoma of the lung and their application to tumor diagnosis. Kyoizumi, S., Akiyama, M., Kouno, N., Kobuke, K., Hakoda, M., Jones, S.L., Yamakido, M. Cancer Res. (1985) [Pubmed]
  8. CD44 interaction with Na+-H+ exchanger (NHE1) creates acidic microenvironments leading to hyaluronidase-2 and cathepsin B activation and breast tumor cell invasion. Bourguignon, L.Y., Singleton, P.A., Diedrich, F., Stern, R., Gilad, E. J. Biol. Chem. (2004) [Pubmed]
  9. Characterization of promoter elements of the human HYAL-2 gene. Chow, G., Knudson, W. J. Biol. Chem. (2005) [Pubmed]
  10. Identification of Hyal2 as the cell-surface receptor for jaagsiekte sheep retrovirus and ovine nasal adenocarcinoma virus. Miller, A.D. Curr. Top. Microbiol. Immunol. (2003) [Pubmed]
  11. HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of specificity. Lepperdinger, G., Strobl, B., Kreil, G. J. Biol. Chem. (1998) [Pubmed]
  12. Expression and activity of hyaluronidase in human periodontal ligament fibroblasts. Ohno, S., Ijuin, C., Doi, T., Yoneno, K., Tanne, K. J. Periodontol. (2002) [Pubmed]
  13. Genetic deletions in sputum as diagnostic markers for early detection of stage I non-small cell lung cancer. Li, R., Todd, N.W., Qiu, Q., Fan, T., Zhao, R.Y., Rodgers, W.H., Fang, H.B., Katz, R.L., Stass, S.A., Jiang, F. Clin. Cancer Res. (2007) [Pubmed]
  14. Envelope-induced cell transformation by ovine betaretroviruses. Alberti, A., Murgia, C., Liu, S.L., Mura, M., Cousens, C., Sharp, M., Miller, A.D., Palmarini, M. J. Virol. (2002) [Pubmed]
  15. Association of RON tyrosine kinase with the Jaagsiekte sheep retrovirus envelope glycoprotein. Varela, M., Chow, Y.H., Sturkie, C., Murcia, P., Palmarini, M. Virology (2006) [Pubmed]
  16. Ability of hyaluronidase 2 to degrade extracellular hyaluronan is not required for its function as a receptor for jaagsiekte sheep retrovirus. Vigdorovich, V., Miller, A.D., Strong, R.K. J. Virol. (2007) [Pubmed]
  17. Structural organization and chromosomal localization of Hyal2, a gene encoding a lysosomal hyaluronidase. Strobl, B., Wechselberger, C., Beier, D.R., Lepperdinger, G. Genomics (1998) [Pubmed]
  18. Enhanced levels of hyaluronan in lungs of patients with COPD: relationship with lung function and local inflammation. Dentener, M.A., Vernooy, J.H., Hendriks, S., Wouters, E.F. Thorax (2005) [Pubmed]
  19. Expression of HYAL2 mRNA, hyaluronan and hyaluronidase in B-cell non-Hodgkin lymphoma: relationship with tumor aggressiveness. Bertrand, P., Courel, M.N., Maingonnat, C., Jardin, F., Tilly, H., Bastard, C. Int. J. Cancer (2005) [Pubmed]
  20. Hyaluronan content of Wharton's jelly in healthy and Down syndrome fetuses. Raio, L., Cromi, A., Ghezzi, F., Passi, A., Karousou, E., Viola, M., Vigetti, D., De Luca, G., Bolis, P. Matrix Biol. (2005) [Pubmed]
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