期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 71, 期 22, 页码 4457-4470出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-014-1629-9
关键词
Heparanase; Uptake; Syndecan; Cytoplasmic tail; Processing
资金
- Israel Science Foundation [593/10]
- National Cancer Institute, NIH [CA106456]
- Israel Cancer Research Fund (ICRF)
- German-Israeli Foundation for Scientific Research and Development (GIF)
- Rappaport Family Institute Fund
Heparanase activity plays a decisive role in cell dissemination associated with cancer metastasis. Cellular uptake of heparanase is considered a pre-requisite for the delivery of latent 65-kDa heparanase to lysosomes and its subsequent proteolytic processing and activation into 8- and 50-kDa protein subunits by cathepsin L. Heparan sulfate proteoglycans, and particularly syndecan, are instrumental for heparanase uptake and activation, through a process that has been shown to occur independent of rafts. Nevertheless, the molecular mechanism underlying syndecan-mediated internalization outside of rafts is unclear. Here, we examined the role of syndecan-1 cytoplasmic domain in heparanase processing, utilizing deletion constructs lacking the entire cytoplasmic domain (Delta), the conserved (C1 or C2), or variable (V) regions. Heparanase processing was markedly increased following syndecan-1 over-expression; in contrast, heparanase was retained at the cell membrane and its processing was impaired in cells over-expressing syndecan-1 deleted for the entire cytoplasmic tail. We have next revealed that conserved domain 2 (C2) and variable (V) regions of syndecan-1 cytoplasmic tail mediate heparanase processing. Furthermore, we found that syntenin, known to interact with syndecan C2 domain, and alpha actinin are essential for heparanase processing.
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