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J. Biol. Chem., Vol. 281, Issue 33, 23804-23811, August 18, 2006

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Characterization of Mechanisms Involved in Secretion of Active Heparanase^*

From the Cancer and Vascular Biology Research Center, the Bruce Rappaport Faculty of Medicine, Technion, Haifa 31096, Israel

Heparanase is an endo--D-glucuronidase involved in extracellular matrix remodeling and degradation and implicated in tumor metastasis, angiogenesis, inflammation, and autoimmunity. The enzyme is synthesized as a latent 65-kDa protein and is processed in the lysosomal compartment to an active 58-kDa heterodimer, where it is stored in a stable form. In contrast, its heparan sulfate substrate is localized extracellularly, suggesting the existence of mechanisms that trigger heparanase secretion. Here we show that secretion of the active enzyme is mediated by the protein kinase A and C pathways. Moreover, secretion of active heparanase was observed upon cell stimulation with physiological concentrations of adenosine, ADP, and ATP, as well as by the noncleavable ATP analogue adenosine 5'-O-(thiotriphosphate). Indeed, heparanase secretion was noted upon cell stimulation with a specific P2Y1 receptor agonist and was inhibited by P2Y receptor antagonists. The kinetics of heparanase secretion resembled the secretion of cathepsin D, a lysosomal enzyme, indicating that the secreted heparanase is of lysosomal origin. We suggest that secretion of active heparanase is initiated by extracellular cues activating the protein kinase A and C signaling pathways. The secreted enzyme(s) then facilitate cell invasion associated with cancer metastasis, angiogenesis, and inflammation.

Received for publication, March 23, 2006 , and in revised form, May 31, 2006.

^* This work was supported by Israel Science Foundation Grant 532/02, NCI, National Institutes of Health, Grant RO1-CA106456, the US-Israel Binational Science Foundation (BSF), and the Rappaport Family Institute Fund. 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.

¹ To whom correspondence should be addressed: Cancer and Vascular Biology Research Center, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. Tel.: 972-4-8295410; Fax: 972-4-8510445; E-mail: vlodavsk{at}cc.huji.ac.il.

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