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J. Biol. Chem., Vol. 279, Issue 42, 44084-44092, October 15, 2004

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Heparanase Uptake Is Mediated by Cell Membrane Heparan Sulfate Proteoglycans^*

Svetlana Gingis-Velitski, Anna Zetser, Victoria Kaplan, Olga Ben-Zaken, Esti Cohen, Flonia Levy-Adam, Yulia Bashenko, Moshe Y. Flugelman¶, Israel Vlodavsky||, and Neta Ilan

From the Cancer and Vascular Biology Research Center, 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 intrachain sites, an activity that is strongly implicated in cell dissemination associated with metastasis and inflammation. In addition to its structural role in extracellular matrix assembly and integrity, HS sequesters a multitude of polypeptides that reside in the extracellular matrix as a reservoir. A variety of growth factors, cytokines, chemokines, and enzymes can be released by heparanase activity and profoundly affect cell and tissue function. Thus, heparanase bioavailability, accessibility, and activity should be kept tightly regulated. We provide evidence that HS is not only a substrate for, but also a regulator of, heparanase. Addition of heparin or xylosides to cell cultures resulted in a pronounced accumulation of, heparanase in the culture medium, whereas sodium chlorate had no such effect. Moreover, cellular uptake of heparanase was markedly reduced in HS-deficient CHO-745 mutant cells, heparan sulfate proteoglycan-deficient HT-29 colon cancer cells, and heparinase-treated cells. We also studied the heparanase biosynthetic route and found that the half-life of the active enzyme is 30 h. This and previous localization studies suggest that heparanase resides in the endosomal/lysosomal compartment for a relatively long period of time and is likely to play a role in the normal turnover of HS. Co-localization studies and cell fractionation following heparanase addition have identified syndecan family members as candidate molecules responsible for heparanase uptake, providing an efficient mechanism that limits extracellular accumulation and function of heparanase.

Received for publication, February 26, 2004 , and in revised form, July 22, 2004.

^* This work was supported by Grant 532/02 from the Israel Science Foundation; by United States Public Health Service Grant RO1 CA106456-01 from NCI, National Institutes of Health; by the Israel Cancer Research Fund; and by a charitable fund established in memory of 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.

Both authors contributed equally to this work.

^|| To whom correspondence should be addressed: Cancer and Vascular Biology Research Center, Faculty of Medicine, Technion, P. O. Box 9649, Haifa 31096, Israel. Tel.: 972-4-829-5410; Fax: 972-4-852-3947; E-mail: vlodavsk{at}cc.huji.ac.il.

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