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J. Biol. Chem., Vol. 279, Issue 22, 23536-23541, May 28, 2004

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Heparanase Induces Endothelial Cell Migration via Protein Kinase B/Akt Activation^*

Svetlana Gingis-Velitski, Anna Zetser, Moshe Y. Flugelman, Israel Vlodavsky¶, and Neta Ilan

From the Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel and the Department of Cardiology, Lady Davis Carmel Medical Center, Haifa 34632, Israel

Heparanase is a mammalian endoglycosidase that degrades heparan sulfate (HS) at specific intra-chain sites. Blood-borne neutrophils, macrophages, mast cells, and platelets exhibit heparanase activity that is thought to be stored in specific granules. The degranulated heparanase is implicated in extravasation of metastatic tumor cells and activated cells of the immune system. Degranulation and heparanase release in response to an inflammatory stimulus or platelet activation would facilitate cellular extravasation directly, by altering the composition and structural integrity of the extracellular matrix, or indirectly, by releasing HS-bound proinflammatory cytokines and chemokines. We hypothesized that in addition to such indirect effect, the released heparanase may also locally affect and activate neighboring cells such as endothelial cells. Here, we provide evidence that addition of the 65-kDa latent heparanase to endothelial cells enhances Akt signaling. Heparanase-mediated Akt phosphorylation was independent of its enzymatic activity or the presence of cell membrane HS proteoglycans and was augmented by heparin. Moreover, addition of heparanase stimulated phosphatidylinositol 3-kinase-dependent endothelial cell migration and invasion. These results suggest, for the first time, that heparanase activates endothelial cells and elicits angiogenic responses directly. This effect appears to be mediated by as yet unidentified heparanase receptor.

Received for publication, January 20, 2004 , and in revised form, March 15, 2004.

^* This work was supported by grants from the Israel Science Foundation (Grant 503/98), The Prostate Cancer Foundation, The Israel Cancer Reserach Fund (ICRF), and by a charitable fund established in memory of the beloved Rachel Litvin. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Cancer and Vascular Biology Research Center, Faculty of Medicine, Technion, P. O. Box 9649, Haifa 31096, Israel, Tel.: 972-4-8295410; Fax: 972-4-8523947; E-mail: vlodavsk{at}cc.huji.ac.il.

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