Fig. 8. Uptake, activation and trafficking of extracellular heparanase precursor. Heparanase precursor binds to the plasma membrane via HSPGs and additional putative receptor(s). The 65 kDa enzyme is processed on (or adjacent to) the cell surface, independently of HSPGs. Uptake occurs within 60 minutes, with accumulation of the processed 50 kDa form in endosomes. Heparanase endocytosis depends on the actin cytoskeleton and HSPGs, and may be inhibited by the N-terminal pro-peptide. Apparently, heparanase endocytosis and processing are two independent events. Following endocytosis, heparanase-containing granules are stored within the cell for a prolonged period. These events may control the activation, clearance and storage of extracellular heparanase.