Technion Integrated Cancer Center (TICC), Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Department of Chemistry, Wayne State University, Detroit, Michigan.
Semin Thromb Hemost. 2021 Apr;47(3):240-253. doi: 10.1055/s-0041-1725066. Epub 2021 Apr 1.
Cell surface proteoglycans are important constituents of the glycocalyx and participate in cell-cell and cell-extracellular matrix (ECM) interactions, enzyme activation and inhibition, and multiple signaling routes, thereby regulating cell proliferation, survival, adhesion, migration, and differentiation. Heparanase, the sole mammalian heparan sulfate degrading endoglycosidase, acts as an "activator" of HS proteoglycans, thus regulating tissue hemostasis. Heparanase is a multifaceted enzyme that together with heparan sulfate, primarily syndecan-1, drives signal transduction, immune cell activation, exosome formation, autophagy, and gene transcription via enzymatic and nonenzymatic activities. An important feature is the ability of heparanase to stimulate syndecan-1 shedding, thereby impacting cell behavior both locally and distally from its cell of origin. Heparanase releases a myriad of HS-bound growth factors, cytokines, and chemokines that are sequestered by heparan sulfate in the glycocalyx and ECM. Collectively, the heparan sulfate-heparanase axis plays pivotal roles in creating a permissive environment for cell proliferation, differentiation, and function, often resulting in the pathogenesis of diseases such as cancer, inflammation, endotheliitis, kidney dysfunction, tissue fibrosis, and viral infection.
细胞表面蛋白聚糖是糖萼的重要组成部分，参与细胞-细胞和细胞-细胞外基质（ECM）的相互作用、酶的激活和抑制以及多种信号通路，从而调节细胞的增殖、存活、黏附、迁移和分化。肝素酶是唯一的哺乳动物硫酸乙酰肝素降解内切糖苷酶，作为 HS 蛋白聚糖的“激活剂”，从而调节组织止血。肝素酶是一种多方面的酶，与硫酸乙酰肝素一起，主要与 syndecan-1 一起，通过酶和非酶活性驱动信号转导、免疫细胞激活、外泌体形成、自噬和基因转录。一个重要的特征是肝素酶能够刺激 syndecan-1 的脱落，从而影响其起源细胞局部和远处的细胞行为。肝素酶释放出大量与 HS 结合的生长因子、细胞因子和趋化因子，这些因子被糖萼和 ECM 中的硫酸乙酰肝素所隔离。总的来说，硫酸乙酰肝素-肝素酶轴在为细胞增殖、分化和功能创造有利环境方面发挥着关键作用，这通常导致疾病的发病机制，如癌症、炎症、血管内皮炎、肾功能障碍、组织纤维化和病毒感染。
