Cellular uptake of mammalian heparanase precursor involves low density lipoprotein receptor-related proteins, mannose 6-phosphate receptors, and heparan sulfate proteoglycans.
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.
Vreys
Veronique
V
Laboratory for Glycobiology and Developmental Genetics, Department of Human Genetics, University of Leuven and Flanders Interuniversity Institute for Biotechnology, 3000 Leuven, Belgium.
Delande
Nathalie
N
Zhang
Zhe
Z
Coomans
Christien
C
Roebroek
Anton
A
Dürr
Joachim
J
David
Guido
G
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002461:Cell Line, Transformed; D006224:Cricetinae; D003412:Cricetulus; D011992:Endosomes / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005966:Glucuronidase / Q000378:metabolism*; D006031:Glycosylation; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D000099175:Heparanase
D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D026502:LDL-Receptor Related Proteins; D011498:Protein Precursors; D017527:Receptor, IGF Type 2; D011994:Recombinant Proteins; D000099175:Heparanase