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J. Biol. Chem., Vol. 282, Issue 28, 20523-20533, July 13, 2007

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Regulation of Secreted Frizzled-related Protein-1 by Heparin^*

Xiaotian Zhong¹, Thamara Desilva, Laura Lin, Peter Bodine, Ramesh A. Bhat, Eleonora Presman, Jennifer Pocas, Mark Stahl, and Ron Kriz

From the Department of Chemical and Screening Sciences, Wyeth Research, Cambridge, Massachusetts 02140 and the Department of Women's Health & Musculoskeletal Biology, Wyeth Research, Collegeville, Pennsylvania 19426

Secreted Frizzled-related protein-1 (sFRP-1) belongs to a class of extracellular antagonists that modulate Wnt signaling pathways by preventing ligand-receptor interactions among Wnts and Frizzled membrane receptor complexes. sFRP-1 and Wnts are heparin-binding proteins, and their interaction can be stabilized by heparin in vitro. Here we report that heparin can specifically enhance recombinant sFRP-1 accumulation in a cell type-specific manner. The effect requires O-sulfation in heparin, and involves fibroblast growth factor-2 as well as fibroblast growth factor receptor-1. Interestingly, further investigation uncovers that heparin can also affect the post-translational modification of sFRP-1. We demonstrate that sFRP-1 is post-translationally modified by tyrosine sulfation at tyrosines 34 and 36, which is inhibited by the treatment of heparin. The results suggest that accumulation of sFRP-1 induced by heparin is in part due to the relative stabilization of unsulfated sFRP-1 and the direct stabilization by heparin. The study has revealed a multifaceted regulation on sFRP-1 protein by heparin.

Received for publication, September 26, 2006 , and in revised form, April 6, 2007.

This paper is dedicated to Prof. Haoran Jian (1911-2007) (by X. Z.).

^* 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: 200 Cambridge Park Dr., Cambridge, MA 02140. Tel.: 617-665-5172; Fax: 617-665-5419; E-mail: xzhong{at}wyeth.com.

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