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J. Biol. Chem., Vol. 280, Issue 50, 41201-41206, December 16, 2005

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Processing by Convertases Is Not Required for Glypican-3-induced Stimulation of Hepatocellular Carcinoma Growth^*

From the Division of Molecular and Cell Biology, Sunnybrook & Women's College Health Sciences Centre and Department of Medical Biophysics, University of Toronto, Ontario M4N 3M5, Canada

Glypicans are a family of heparan sulfate proteoglycans that are bound to the cell surface by a lipid anchor. Six members of this family have been identified in mammals (GPC1-GPC6). Glypicans act as regulators of the activity of various cytokines, including Wnts, Hedgehogs, and bone morphogenetic proteins. It has been reported that processing by a convertase is required for GPC3 activity during convergent extension in zebrafish embryos, for GPC3-induced regulation of Wnt signaling, and for the binding of GPC3 to Wnt5a. In our laboratory, we have recently demonstrated that GPC3 promotes the growth of hepatocellular carcinomas (HCCs) by stimulating canonical Wnt signaling. Because there is increasing evidence indicating that the structural requirements for GPC3 activity are cell type specific, we decided to investigate whether GPC3 needs to be processed by convertases to stimulate cell proliferation and Wnt signaling in HCC cells. We report here that a mutant GPC3 that cannot be processed by convertases is still able to play its stimulatory role in Wnt activity and HCC growth.

Received for publication, June 27, 2005 , and in revised form, August 29, 2005.

^* This work was supported by a grant from the Canadian Institutes of Health Research. 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: Division of Molecular and Cell Biology, Sunnybrook & Women's College Health Sciences Centre, 2075 Bayview Ave., Rm. S-220, Toronto, Ontario M4N 3M5, Canada. Tel.: 416-480-6100 (ext. 3350); Fax: 416-480-5703; E-mail: jorge.filmus{at}swri.ca.