4.4 Article

Biology of the Heparanase-Heparan Sulfate Axis and Its Role in Disease Pathogenesis

期刊

SEMINARS IN THROMBOSIS AND HEMOSTASIS
卷 47, 期 3, 页码 240-253

出版社

THIEME MEDICAL PUBL INC
DOI: 10.1055/s-0041-1725066

关键词

heparanase; syndecan; glycocalyx; signal transduction; exosomes

资金

  1. National Institutes of Health [CA211752, R01GM098285]
  2. United States-Israel Binational Science Foundation (BSF)
  3. Israel Science Foundation [601/14, 1021/19]
  4. ISF-NSFC joint research program [2572/16]
  5. Israel Cancer Research Fund (ICRF)

向作者/读者索取更多资源

Cell surface proteoglycans play crucial roles in regulating various cellular functions, such as proliferation, survival, adhesion, migration, and differentiation, through interactions with the extracellular environment. Heparanase, as a key enzyme involved in this process, is responsible for modulating tissue hemostasis and diverse cellular activities, ultimately contributing to the pathogenesis of diseases.
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.

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