Heparanase induces Akt phosphorylation via a lipid raft receptor

Abstract

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.

Characterization of Heparanase-induced Phosphatidylinositol 3-Kinase-AKT Activation and Its Integrin Dependence

“…Binding studies with heparanase have suggested that a high affinity binding site for heparanase exists on many cell types and strongly support the existence of a specific heparanase receptor(s) (11,14). Several key features of the mechanism of AKT activation triggered by the putative receptor were identified in the present study.…”

“…Evidence indicates that this receptor(s) is localized to lipid rafts, based on the inhibitory effect of cholesterol-depleting agents on heparanase signaling (14). Different proteins that have been suggested as heparanase receptors include mannose 6-phosphate receptor and low density lipoprotein receptor-related protein (15).…”

“…Different proteins that have been suggested as heparanase receptors include mannose 6-phosphate receptor and low density lipoprotein receptor-related protein (15). However, heparanase efficiently activates AKT in cells where these proteins have been knocked out, and therefore the identity of the receptor(s) remains unknown (14). Furthermore, the mechanisms by which the heparanase receptor(s) activates its downstream mediators have not been fully characterized.…”

Halofuginone upregulates the expression of heparanase in thioacetamide-induced liver fibrosis in rats

“…9,35 Heparanase has also been shown to exert non-enzymatic effects, including phosphorylation of a number of factors. 36,37 Its translocation to the nucleus in various cell types may be an additional, potential, mechanism affecting gene transcription. 38 We have documented a biphasic gain of heparanase expression during liver regeneration following 70% PHx.…”

Heparanase expression by Barrett's epithelium and during esophageal carcinoma progression

“…[31][32][33] The significance of this observation critically emerges from recent studies showing that secreted heparanase augments signal transduction pathways, leading to activation of certain protein kinases (that is, Akt, Src, EGFR) and increased gene transcription (that is, VEGF, TF, COX2) associated with enhanced tumor progression. 21,28,[34][35][36][37][38][39] Previous studies have shown that heparanase also assumes nuclear localization, 40,41 and that nuclear heparanase is associated with a favorable prognosis of head and neck, gastric, and esophageal cancer patients. 20,[41][42][43] It was unclear, however, at what stage of tumor initiation/progression nuclear translocation takes place.…”