Activation, processing and trafficking of extracellular heparanase by primary human fibroblasts
2002
Heparanase is a heparan-sulfate-degrading endoglycosidase that has
important roles in various biological processes, including angiogenesis, wound
healing and metastatsis. Human heparanase is synthesized as a 65 kDa latent
precursor, which is proteolytically processed into a highly active 50 kDa
form. Extracellular heparanase is found in various tissues and is utilized by
both normal cells and metastatic cancer cells to degrade heparan sulfate
moieties in basement membranes and extracellular matrices. This study
characterizes the processing and trafficking events associated with cellular
activation of extracellular heparanase. We show that primary human fibroblasts
are capable of binding and converting the 65 kDa heparanase precursor into its
highly active 50 kDa form, concomitantly with its cytoplasmic accumulation.
Heparanase uptake depends on the actin cytoskeleton integrity, resulting in a
prolonged storage of the enzyme, mainly in endosomal structures. Heparanase
endocytosis and its proteolytic activation are independent processes,
indicating that heparanase cleavage is a cell surface event. Heparin
completely inhibits heparanase endocytosis but only partially inhibits its
association with the cells, suggesting that cell surface heparan sulfate
moieties play a specific role in its endocytosis. Cellular binding and uptake
of extracellular heparanase control its activation, clearance rate and storage
within the cells.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
50
References
87
Citations
NaN
KQI