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J. Biol. Chem., Vol. 279, Issue 17, 17535-17542, April 23, 2004

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The Low Density Lipoprotein Receptor-1, LRP1, Interacts with the Human Frizzled-1 (HFz1) and Down-regulates the Canonical Wnt Signaling Pathway^*

Alona Zilberberg, Abraham Yaniv, and Arnona Gazit

From the Department of Human Microbiology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

Members of the low density lipoprotein receptor family (LDLR), LRP5/6, were shown to interact with the Frizzled (Fz) receptors and to function as Wnt coreceptors. Here we show that mLRP4T100, a minireceptor of LRP1, another member of the LDLR family, interacts with the human Fz-1 (HFz1), previously shown to serve as a receptor transmitting the canonical Wnt-3a-induced signaling cascade. However, in contrast to LRP5/6, mLRP4T100, as well as the full-length LRP1, did not cooperate with HFz1 in transmitting the Wnt-3a signaling but rather repressed it. mLRP4T100 inhibitory effect was displayed also by endocytosis-defective mLRP4T100 mutants, suggesting that LRP1 repressive effect is not attributable to LRP1-mediated enhanced HFz1 internalization and subsequent degradation. Enforced expression of mLRP4T100 decreased the capacity of HFz1 cysteine-rich domain (CRD) to interact with LRP6, in contrast to HFz1-CRD/Wnt-3a interaction that was not disrupted by overexpressing mLRP4T100. These data suggest that LRP1, by sequestering HFz1, disrupts the receptor/coreceptor complex formation, leading to the repression of the canonical Wnt signaling. Thus, this study implies that the ability to interact with Fz receptors is shared by several members of the LDLR family. However, whereas some members of the LDLR family, such as LRP5/6, interact with Fz and serve as Wnt coreceptors, others negatively regulate Wnt signaling, presumably by sequestering Fz.

Received for publication, October 14, 2003 , and in revised form, January 21, 2004.

^* This work was supported by grants from the United States-Israel Binational Science Foundation, Israel Science Foundation founded by The Israel Academy of Science and Humanities, Israel Ministry of Health, Recanati Fund for Medical Research, and Tel Aviv University Research 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.

This work is in partial fulfillment of the requirements for the Ph.D. degree from the Sackler School of Medicine at Tel Aviv University.

To whom correspondence should be addressed. Tel.: 972-3-640-9869; Fax: 972-3-642-2275; E-mail: micro1{at}post.tau.ac.il.

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