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J. Biol. Chem., Vol. 279, Issue 23, 24659-24665, June 4, 2004

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Multiple Mechanisms for Wnt11-mediated Repression of the Canonical Wnt Signaling Pathway^*

Peter Maye, Jie Zheng, Lin Li, and Dianqing Wu¶

From the Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, the Department of Structural Biology, St. Jude Hospital, Memphis Tennessee 38105, and the Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China 200031

The effect of a noncanonical Wnt, Wnt11, on canonical Wnt signaling stimulated by Wnt1 and activated forms of LRP5 (low density lipoprotein receptor-related protein-5), Dishevelled1 (Dvl1), and -catenin was examined in NIH3T3 cells and P19 embryonic carcinoma cells. Wnt11 repressed Wnt1-mediated activation of LEF-1 reporter activity in both cell lines. However, Wnt11 was unable to inhibit canonical signaling activated by LRP5, Dvl1, or -catenin in NIH3T3 cells, although it could in P19 cells. In addition, Wnt11-mediated inhibition of canonical signaling in NIH3T3 cells is ligand-specific; Wnt11 could effectively repress canonical signaling activated by Wnt1, Wnt3, or Wnt3a but not by Wnt7a or Wnt7b. Co-culture experiments with NIH3T3 cells showed that the co-expression of Wnt11 with Wnt1 was not an essential requirement for the inhibition, suggesting receptor competition as a possible mechanism. Moreover, in both cell types, elevation of intracellular Ca²⁺ levels, which can result from Wnt11 treatment, led to the inhibition of canonical signaling. This result suggests that Wnt11 might not be able to signal in NIH3T3. Furthermore, P19 cells were found to express both endogenous canonical Wnts and Wnt11. Knockdown of Wnt11 expression using siRNA resulted in increased LEF-1 reporter activity, thus indicating that Wnt11-mediated suppression of canonical signaling exists in vivo.

Received for publication, October 24, 2003 , and in revised form, March 15, 2004.

^* This work is supported by Grants GM54167 and CA85420 from the National Institutes of Health (to D. W.). 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.

^¶ An Established Investigator of American Heart Association. To whom correspondence should be addressed: Dept. of Genetics and Developmental Biology, University of Connecticut Health Center, MC3301, 263 Farmington Ave., Farmington, CT 06030. Tel.: 860-679-8818; Fax: 860-679-1024; E-mail: dwu{at}neuron.uchc.edu.

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