Abstract
Mammalian heparanase, strongly implicated in the regulation of cell growth, migration, and differentiation, plays a crucial role in inflammation, angiogenesis, and metastasis. There is thus a clear need for understanding how heparanase activity is regulated. Cells can generate an active form of the enzyme from a larger inactive precursor protein by a process of secretion-recapture, internalization, and proteolytic processing in late endosomes/lysosomes. Cell surface heparan sulfate proteoglycans are the sole known components with a role in this trafficking of the heparanase precursor. Here, we provide evidence that heparan sulfate proteoglycans are not strictly required for this process. More importantly, by heparanase transfection, binding, and uptake experiments and by using a combination of specific inhibitors and receptor-defective cells, we have identified low density lipoprotein receptor-related proteins and mannose 6-phosphate receptors as key elements of the receptor system that mediates the capture of secreted heparanase precursor and its trafficking to the intracellular site of processing/activation.
Highlights
Heparan sulfate proteoglycans (HSPGs)3 play a key role in the selfassembly of extracellular matrices and sequester a variety of growth factors, cytokines, chemokines, and coagulation factors in these support structures [1]
We found that low density lipoprotein receptor-related protein (LRP) and possibly other receptor-associated protein (RAP)-sensitive receptor(s), as well as mannose 6-phosphate (Man6-P) receptors are key to this process
Man-6-P Receptor Involvement in Heparanase-1 Precursor Uptake —As most of the soluble lysosomal hydrolases are transported via Man6-P receptors [27], we investigated whether this receptor system might play a role in the capture or recapture of heparanase-1
Summary
Heparan sulfate proteoglycans (HSPGs)3 play a key role in the selfassembly of extracellular matrices and sequester a variety of growth factors, cytokines, chemokines, and coagulation factors in these support structures [1]. Consistent with a possible role for HSPG in heparanase-1 uptake or reuptake, HS-deficient CHO 677 cells [20] that were transiently transfected with heparanase-1 released large amounts of the ϳ65-kDa heparanase-1 precursor into their culture medium (Fig. 2A, lane 4).
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