Hyaluronan synthase
Hyaluronan synthases (HAS) are membrane-bound enzymes which use UDP-α-N-acetyl-D-glucosamine and UDP-α-D-glucuronate as substrates to produce the glycosaminoglycan hyaluronan at the cell surface and extrude it through the membrane into the extracellular space.
Isoforms
There are three mammalian hyaluronan synthases described to date - HAS1, HAS2 and HAS3. Each of these isoforms resides at a different chromosome location[1] and has been cloned.[2] Two of the main differences between the isoforms are the chain length of the hyaluronan molecules that they produce and the ease with which they can be released from the cell surface.[3][4] When mammalian cells are stimulated by changes in their immediate environment (cytokines, extracellular matrix proximities), the HAS isoforms respond differently and appear to be under different control mechanisms.
During the development of the embryo, each isoform is uniquely expressed, both spatially and temporally.
- HAS2 is probably the most important synthase at this time as mice lacking the ability to express HAS2 (knock-out mice) die at mid-gestation,[5]
- HAS1 or HAS3 knock-out mice show no effect on foetal development,[6].
Role in Cancer Metastasis
HAS can play roles in all of the stages of cancer metastasis. By producing anti-adhesive HA, HAS can allow tumor cells to release from the primary tumor mass and if HA associates with receptors such as CD44, the activation of Rho GTPases can promote EMT of the cancer cells. During the processes of intravasation or extravasation, the interaction of HAS produced HA with receptors such as CD44 or RHAMM promote the cell changes that allow for the cancer cells to infiltrate the vascular or lymphatic systems. While traveling in these systems, HA produced by HAS protects the cancer cell from physical damage. Finally, in the formation of a metastatic lesion, HAS produces HA to allow the cancer cell to interact with native cells at the secondary site and to produce a tumor for itself.[7]
Increased HA production by cancer cells increases invasive capacity. HA's interaction with CD44 activates focal adhesion kinase (FAK), an important molecule in the process of cell motility by coordinating dissolution of the focal adhesions at the leading edge of the cell and formation at the lagging edge.[8] Another signaling pathway activated by HA's interaction with CD44 is the Akt pathway which leads to expression of osteopontin, a molecule which can stimulate cell migration.[9] The HA produced by HAS also has been suggested to protect the cancer cell from physical damage while in the circulatory or lymphatic systems. This role of HA has been shown in other cell types, but has not yet been researched in cancer cells.[10] The HA produced by HAS up-regulates secretion of various MMPs, proteolytic enzymes that are involved in many stages of the metastatic cascade.[11] Research has shown that the different HASs may impact the metastatic steps in different ways based on the molecular weight and amount of HA they produce.
References
- ↑ Spicer AP et al. (1997) Chromosomal localization of the human and mouse hyaluronan synthase genes. Genomics 41:493-497.
- ↑ Itano N and Kimata K (2002) Mammalian hyaluronan synthases. IUBMB Life 54:195-199.
- ↑ Itano N et al. (1999) Three isoforms of mammalian hyaluronan synthases have distinct enzymatic properties. J Biol Chem 274:25085-25092.
- ↑ Stern R, et al. (2006) Hyaluronan fragments: an information-rich system. Eur J Cell Biol 85:699-715.
- ↑ Camenisch TD et al. (2000) Disruption of hyaluronan synthase-2 abrogates normal cardiac morphogenesis and hyaluronan-mediated transformation of epithelium to mesenchyme. J Clin Invest 106:349-360.
- ↑ Bai KJ et al. (2005) The role of hyaluronan synthase 3 in ventilator-induced lung injury. Am J Respir Crit Care Med 172(1):92-8.
- ↑ Bharadwaj AG, et al. Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing. Am J Path. 2009;174:1027-1036
- ↑ Fujita Y, et al. CD44 signaling through focal adhesion kinase and its anti-apoptotic effect. FEBS letters. 2002;528:101-108
- ↑ Park JB, et al. Role of hyaluronan in glioma invasion. Cell Adhesion and Migration. 2008;2:202-207
- ↑ Jiang D, et al. Regulation of lung injury and repair by Toll-like receptors and hyaluornan. Nat Med. 2005;11:1173-1179
- ↑ Dunn KM, et al. Inhibition of hyaluronan synthases decreases matrix metalloproteinase-7 (MMP-7) expression and activity. Surgery. 2009;145:32-329
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