Heparanase: A Multitasking Protein Involved in Extracellular Matrix (ECM) Remodeling and Intracellular Events

Abstract

Heparanase (HPSE) has been defined as a multitasking protein that exhibits a peculiar enzymatic activity towards HS chains but which simultaneously performs other non-enzymatic functions. Through its enzymatic activity, HPSE catalyzes the cutting of the side chains of heparan sulfate (HS) proteoglycans, thus contributing to the remodeling of the extracellular matrix and of the basal membranes. Furthermore, thanks to this activity, HPSE also promotes the release and diffusion of various HS-linked molecules like growth factors, cytokines and enzymes. In addition to being an enzyme, HPSE has been shown to possess the ability to trigger different signaling pathways by interacting with transmembrane proteins. In normal tissue and in physiological conditions, HPSE exhibits only low levels of expression restricted only to keratinocytes, trophoblast, platelets and mast cells and leukocytes. On the contrary, in pathological conditions, such as in tumor progression and metastasis, inflammation and fibrosis, it is overexpressed. With this brief review, we intend to provide an update on the current knowledge about the different role of HPSE protein exerted by its enzymatic and non-enzymatic activity.

Cancer Metastasis: The Role of the Extracellular Matrix and the Heparan Sulfate Proteoglycan Perlecan

“…It has also been proposed that reduced adhesion of tumor cells to the underlying ECM, as well as increased cell motility, is due to cleavage of cell surface HS by heparanase produced by the tumor cell itself (108). Notably, heparanase has also been recognized to participate in some non-enzymatic activities, separate from its involvement in ECM degradation and remodeling (199)(200)(201).…”

Heparan Sulfate Proteoglycans Biosynthesis and Post Synthesis Mechanisms Combine Few Enzymes and Few Core Proteins to Generate Extensive Structural and Functional Diversity

“…Extracellular activity of heparanase leads to the loosening of ECM architecture and the release of biologically active HS fragments as well as ECM stored HS ligands such as growth factors, chemokines and morphogens. Based on its multiple activities, heparanase has been associated with a wide range of physiological and pathological processes, including tumor growth, angiogenesis, invasion and chemoresistance, inflammation, fibrosis, coagulation and thrombosis or viral infection [ 208 , 210 , 211 , 212 ]. Noteworthy, heparanase II (Hpa2), a homolog of heparanase, has been identified [ 213 ].…”

Heparanase, cell signaling, and viral infections

“…Heparanase (HPSE) is an endo-β-d-endoglycosidase that is the only known mammalian enzyme able to cleave heparan sulfate (HS) moieties at certain positions [1]. HPSE plays an important role in the degradation and modification of the extracellular matrix (ECM) [2]. It is a 58 kDa heterodimer composed of 50 kDa and 8 kDa subunits which bind noncovalently [2].…”

“…HPSE plays an important role in the degradation and modification of the extracellular matrix (ECM) [2]. It is a 58 kDa heterodimer composed of 50 kDa and 8 kDa subunits which bind noncovalently [2]. The enzyme is initially synthesized in the endoplasmic reticulum as a 68 kDa precursor protein, modified in the Golgi apparatus to become a 65 kDa proenzyme, and transported to the exterior of the cell [3].…”