TMEM2: A missing link in hyaluronan catabolism identified?

Abstract

Hyaluronan (HA) is a glycosaminoglycan (GAG) composed of repeating disaccharide units of glucuronic acid and N-acetylglucosamine. HA is an extremely long, unbranched polymer, which often exceeds 10 Da and sometimes reaches 10 Da. A feature that epitomizes HA is its rapid turnover; one-third of the total body HA is turned over daily. The current model of HA catabolism postulates that high-molecular weight HA in the extracellular space is first cleaved into smaller fragments by a hyaluronidase(s) that resides at the cell surface, followed by internalization of fragments and their degradation into monosaccharides in lysosomes. Over the last decade, considerable research has shown that the HYAL family of hyaluronidases plays significant roles in HA catabolism. Nonetheless, the identity of a hyaluronidase responsible for the initial step of HA cleavage on the cell surface remains elusive, as biochemical and enzymological properties of HYAL proteins are not entirely consistent with those expected of cell surface hyaluronidases. Recent identification of transmembrane 2 (TMEM2) as a cell surface protein that possesses potent hyaluronidase activity suggests that it may be the "missing" cell surface hyaluronidase, and that novel models of HA catabolism should include this protein.

Hyaluronan synthase 2–mediated hyaluronan production mediates Notch1 activation and liver fibrosis

“…In a physiological condition, circulating and hepatic HA concentrations are regulated by the appropriate balance between production and clearance. The half-life of plasma HA is 2.5 to 5.5 min, and one-third of the total body HA is turned over daily (25, 26). LSECs play a prominent role in the elimination of circulating HA in the liver, contributing to the rapid clearance and turnover of HA.…”

Biomimetic tissue models reveal the role of hyaluronan in melanoma proliferation and invasion

“…However, recent data suggest that HYAL1 may support tumor metastasis independently of the generation of small HA-oligosaccharide products thus leaving alternative ways of action conceivable. 34 The prevalence of other HA degrading enzymes, like CEMIP and TMEM2, obviously also correlates with progression or metastasis in tumor patients, 22,35 whereas the small HA-oligosaccharide molecules where not quantified in these studies. Thus, today it remains to prove that really the HA-degradation products are the tumor promoting molecules or whether other mechanisms involving these proteins lead to cancer progression.…”

Neuronal Pentraxin 2 Binds PNNs and Enhances PNN Formation

“…Several enzymes are known to break down the PNN. Both chondroitinase ABC (chABC) [4, 15] and hyaluronidase [16, 17] remove the PNN from the surface of the neurons and induce a renewed capacity for plasticity. For example, when the PNN is removed in the visual cortex, ocular dominance plasticity can be reopened [4].…”