Heparanase induces Akt phosphorylation via a lipid raft receptor.
The endoglycosidase heparanase is the predominant enzyme that degrades heparan sulfate side chains of heparan sulfate proteoglycans, activity that is strongly implicated in tumor metastasis. Apart of its well characterized enzymatic activity, heparanase was noted to exert also enzymatic-independent functions. Among these is the induction of Akt/PKB phosphorylation noted in endothelial- and tumor-derived cells. Protein domains of heparanase required for signaling were not identified to date, nor were identified heparanase binding proteins/receptors capable of transmitting heparanase signals. Here, we examined the possible function of mannose 6-phosphate receptor (MPR) and low-density lipoprotein-receptor related protein (LRP), recently implicated in cellular uptake of heparanase, as heparanase receptors mediating Akt phosphorylation. We found that heparanase addition to MPR- and LRP-deficient fibroblasts elicited Akt activation indistinguishable from control fibroblasts. In contrast, disruption of lipid rafts abrogated Akt/PKB phosphorylation following heparanase addition. These results suggest that lipid raft-resident receptor mediates heparanase signaling.
Ben-Zaken
Olga
O
Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel.
Gingis-Velitski
Svetlana
S
Vlodavsky
Israel
I
Ilan
Neta
N
D000818:Animals; D002478:Cells, Cultured; D006224:Cricetinae; D005966:Glucuronidase / Q000494:pharmacology*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D021962:Membrane Microdomains / Q000187:drug effects / Q000201:enzymology*; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017527:Receptor, IGF Type 2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism*; D000099175:Heparanase
D005966:Glucuronidase; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051057:Proto-Oncogene Proteins c-akt; D017527:Receptor, IGF Type 2; D011956:Receptors, Cell Surface; D000099175:Heparanase
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