(B) Role of HA degradation in tumor cell migration. essential role in systemic HA catabolism in vivo11). Furthermore, the relevance of TMEM2 to cell migration in vivo has been demonstrated by another study using neural crest cell-specific Tmem2 knockout mice12). Together with the current funded project, our studies have established the functional and physiological significance of this novel hyaluronidase. Our future research will focus mainly on two aspects of TMEM2, ReferencesFigure 2. A model for the role of TMEM2 in integrin-namely: (i) the determination of the catalytic mechanism of TMEM2 and the development of TMEM2 inhibitors; and (ii) the phenotypic characterization of the consequence of Tmem2 deletion in vivo using conditional knockout models targeting various adult tissues. Through these studies, we will seek to define the relevance of TMEM2 in human diseases and explore the possibility of TMEM2 as a therapeutic target.mediated cell adhesion and migration (A) FA formation and maturation through HA degradation. High levels of HA in ECM act as a repulsive barrier that interferes with the direct engagement of integrins to their ECM ligands (1). In the presence of TMEM2, HA in the ECM is locally removed, which generates a microenvironment that is permissible to the direct integrin-ECM engagement (2). The association between TMEM2 and integrins promotes the FA formation and maturation via further removal of HA in the vicinity of the integrin-ECM engagement (3). This in turn facilitates integrin clustering, integrin-mediated downstream signaling, and cellular responses (4).TMEM2 hyaluronidase activity drives cell migration through cycling of FA formation and maturation on HA-rich ECM. Sequence of FA development (2, 3, and 4 in panel A) takes place from the leading edge to the cell inward in migrating cell (left). During migration, degraded HA exhibits a steak-like pattern due to movement of FAs (right). 1) Provenzano, P. P., and Hingorani, S. R. (2013) Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer 108, 1-8 2) Chanmee, T., Ontong, P., and Itano, N. (2016) Hyaluronan: A modulator of the tumor microenvironment. Cancer Lett 375, 20-30 3) Stern, R., Kogan, G., Jedrzejas, M. J., and Soltes, L. (2007) The many ways to cleave hyaluronan. Biotechnol Adv 25, 537-557 4) Chow, G., Knudson, C. B., and Knudson, W. (2006) Human hyaluronidase-2 is localized intracellularly in articular chondrocytes and other cultured cell 5) Lepperdinger, G., Strobl, B., and Kreil, G. (1998) HYAL2, a human gene expressed in many cells, encodes a lysosomal hyaluronidase with a novel type of 6) Yamamoto, H., Tobisawa, Y., Inubushi, T., Irie, F., Ohyama, C., and Yamaguchi, Y. (2017) A mammalian homolog of the zebrafish Transmembrane 7) Irie, F., Tobisawa, Y., Murao, A., Yamamoto, H., Ohyama, C., and Yamaguchi, Y. (2021) The cell surface hyaluronidase TMEM2 regulates cell adhesion 8) Tammi, R. H., Kultti, A., Kosma, V. M., Pirinen, R., Auvinen, P., and Tammi, M. I. (2008) Hyaluronan in human tumors: pathobiological and prognostic 9) Lee, H., Goodarzi, H., Tavazoie, S. F., and Alarcon, C. R. (2016) TMEM2 is a SOX4-regulated gene that mediates metastatic migration and invasion in lines. Osteoarthritis Cartilage 14, 1312-1314specificity. J Biol Chem 273, 22466-22470Protein 2 (TMEM2) is the long-sought-after cell surface hyaluronidase. J Biol Chem 292, 7304-7313and migration via degradation of hyaluronan at focal adhesion sites. J Biol Chem 296, 100481messages from cell-associated and stromal hyaluronan. Semin Cancer Biol 18, 288-295breast cancer. Cancer Res 76, 4994-500510) Kudo, Y., Sato, N., Adachi, Y., Amaike, T., Koga, A., Kohi, S., Noguchi, H., Nakayama, T., and Hirata, K. (2020) Overexpression of transmembrane protein 2 (TMEM2), a novel hyaluronidase, predicts poor prognosis in pancreatic ductal adenocarcinoma. Pancreatology 20, 1479-148511) Tobisawa, Y., Fujita, N., Yamamoto, H., Ohyama, C., Irie, F., and Yamaguchi, Y. (2021) The cell surface hyaluronidase TMEM2 is essential for systemic hyaluronan catabolism and turnover. J Biol Chem 297, 10128112) Inubushi, T., Nakanishi, Y., Abe, M., Takahata, Y., Nishiyama, R., Kurosaka, H., Irie, F., Yamashiro, T., and Yamaguchi, Y. (2022) The cell surface hyaluronidase TMEM2 plays an essential role in mouse neural crest cell development and survival. PLoS Genet. 18, e1009765 93
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