Disease relevance of Hyal2

• Role of virus receptor Hyal2 in oncogenic transformation of rodent fibroblasts by sheep betaretrovirus env proteins [1].
• Oncogenic transformation assays using mouse and rat fibroblasts have localized the transforming activity to the Env proteins encoded by these viruses, which require the putative lung and breast cancer tumor suppressor hyaluronidase 2 (Hyal2) to promote virus entry into cells [1].
• Improved enzootic nasal tumor virus pseudotype packaging cell lines reveal virus entry requirements in addition to the primary receptor Hyal2 [2].
• Similarly, all glioblastomas multiforme expressed hyaluronidases MGEA5 and Hyal2 [3].
• Several human glioma cell lines were found to overexpress hyaluronan synthases, but they did so in conjunction with hyaluronidase Hyal2 and MGEA5 expression [3].

High impact information on Hyal2

• Retrovirus entry into cells is mediated by Env interaction with particular cell-surface receptors, and we have used phenotypic screening of radiation hybrid cell lines to identify the candidate lung cancer tumor suppressor HYAL2/LUCA2 as the receptor for JSRV [4].
• However, five rat cell lines from different rat strains and different tissues that were engineered to express human Hyal2 were still only poorly infected by ENTV vectors, even though the ENTV Env protein could bind well to human Hyal2 expressed on four of these cell lines [2].
• In rat and mouse fibroblasts, the cytoplasmic tail of JSRV Env is essential for transformation, which involves activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and the virus receptor hyaluronidase 2 (Hyal2) is not involved [5].
• The cellular receptor for JSRV is hyaluronidase 2 (Hyal-2), the product of a putative tumor suppressor gene that in humans maps to a chromosomal region frequently deleted in the development of lung and breast cancers [6].
• Hyaluronidases such as PH-20, Hyal-1 and Hyal-2 induce the expression of WOX1, and hyaluronidases and hyaluronan are involved in the embryonic development [7].

Biological context of Hyal2

• Current evidence about the role of Hyal2 in tumor growth, inflammation and frog embryogenesis is discussed [8].
• This fragment was used to isolate the Hyal2 cDNA from a cDNA library [9].
• Hyal-2 translocated from the lysosome to the mitochondria during staurosporine-mediated apoptosis, suggesting that Hyal-2 may damage mitochondria [10].
• Finally, Hyal-1 and Hyal-2 blocked TGF-beta1-enhanced L929 cell growth [10].
• However, the most important amino acids map to a small patch on a predicted 3-dimensional Hyal2 structure, which may represent the binding site for Env [11].

Anatomical context of Hyal2

• Originally considered to be a typical lysosomal enzyme, more recent evidence has shown that Hyal2 proteins can also be exposed on the cell surface bound to the plasma membrane via a GPI anchor [8].
• Twenty-kDa hyaluronan fragments are generated at the cell surface in unique endocytic vesicles resulting from digestion by the glycosylphosphatidyl-inositol-anchored Hyal-2, transported intracellularly by an unknown process, and then further digested by Hyal-1 [12].

Other interactions of Hyal2

• RESULTS: Murine L929 fibroblasts were engineered to stably express green-fluorescent protein (GFP)-tagged hyaluronidase (GFP-Hyal-1 or GFP-Hyal-2) or GFP alone [10].
• CONCLUSIONS: TGF-beta1 limits the ability of Hyal-2 to induce TNF cytotoxicity in L929 cells [10].
• Both viruses use the glycosylphosphatidylinositol (GPI)-anchored cell surface protein hyaluronidase 2 (Hyal2) as a receptor for cell entry, and entry is mediated by the envelope (Env) proteins encoded by these viruses [2].

Analytical, diagnostic and therapeutic context of Hyal2

• Regions conserved in these proteins have been used to design PCR primers suitable for the isolation of a fragment of the murine Hyal2 gene [9].

References