Current understanding of heparanase 2 regulation, a non-heparanase

Heparan sulfate (HS) proteoglycans are life-supporting proteins comprising a core protein to which one or more HS glycan chains are covalently bound. HS proteoglycans act as binding sites for circulating cells and molecules, allow gradient formation, and provide local storage capacities. They act as coreceptors, fine-tuning growth factor receptors and activating intracellular signaling pathways. HS glycan chains are cleaved and regulated by heparanase 1 (Hpa1). Heparanase 2 (Hpa2) is a close homolog of Hpa1. Unlike Hpa1, Hpa2 lacks enzymatic activity but nonetheless binds HS with high affinity, thus modulating HS-mediated biological processes. Only a few functions of Hpa2 have been unraveled. Under disease conditions that include the Mendelian urofacial syndrome, Hpa2 expression is markedly down-regulated, most compellingly demonstrated in several cancers. Hpa2 also circulates in the bloodstream, potentially originating from secretory organs such as liver and pancreas. The Hpa2 promotor is inducible by cellular stressors including cytotoxic, proteostatic, and endoplasmic reticulum stress. Activating transcription factor 3 (ATF3) induces Hpa2 gene expression. We summarize Hpa2 regulation in the framework of health and disease to foster research into its function. The underlying mystery remains: ‘How does this “heparanase,” which is actually a non-heparanase, work, and what are the ramifications?