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Mouse Cristin/R-spondin Family Proteins Are Novel Ligands for the Frizzled 8 and LRP6 Receptors and Activate beta-Catenin-dependent Gene Expression

Nam, Ju-Suk and Turcotte, Taryn J. and Smith, Peter F. and Choi, Sangdun and Yoon, Jeon Kyo (2006) Mouse Cristin/R-spondin Family Proteins Are Novel Ligands for the Frizzled 8 and LRP6 Receptors and Activate beta-Catenin-dependent Gene Expression. Journal of Biological Chemistry, 281 (19). pp. 13247-13257. ISSN 0021-9258. doi:10.1074/jbc.M508324200.

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Wnt signaling plays critical biological roles during normal embryonic development and homeostasis in adults. In the canonical pathway, binding of Wnt ligands to the Frizzled (Fzd) receptor and the low density lipoprotein-related receptor (LRP) 5 or LRP6 coreceptor initiates downstream signaling events leading to gene activation by beta-catenin and the T-cell factor (TCF)-lymphoid enhancer factor (LEF) family transcription factor complex. In this study, we provide several lines of evidence that the mouse Cristin/R-spondin family proteins function as Fzd8 and LRP6 receptor ligands and induce the canonical Wnt/beta-catenin signaling pathway, leading to TCF-dependent gene activation. First, conditioned medium containing Cristin/R-spondin proteins effectively induced reporter activity in a TCF-binding site-dependent manner. Second, stimulation of cells with Cristin/R-spondin was accompanied by stabilization of endogenous beta-catenin proteins and induction of canonical Wnt target genes. Third, Cristin/R-spondin proteins physically interacted with the extracellular domains of the LRP6 and Fzd8 receptors in vivo and in vitro. Interestingly, unlike canonical Wnt ligands, Cristin/R-spondin failed to form a ternary complex with both LRP6 and Fzd8 receptors, suggesting that R-spondin may activate the canonical Wnt signaling pathway by different mechanisms. Furthermore, Cristin/R-spondin proteins possess an intriguing positive modulatory activity on Wnt ligands, possibly through a direct interaction. Our findings expand the repertoire of ligands that induce beta-catenin/TCF-dependent gene activation and implicate the presence of active beta-catenin-dependent gene activation in a Wnt-free biological context.

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Additional Information:© 2006 the American Society for Biochemistry and Molecular Biology. Received for publication, July 29, 2005 , and in revised form, March 2, 2006. Originally published In Press as doi:10.1074/jbc.M508324200 on March 16, 2006 We thanks Drs. Robert Friesel, Lucy Liaw, Leif Oxburgh, Doug Spicer, and Don Wojchowski for critical reading of and comments on the manuscript and Norma Albrecht for proofreading. We are indebted to Drs. Rudolf Grosschedl, Xi He, Jen-Chih Hsieh, Nobue Itasaki, Randall Moon, Christof Niehrs, and Roel Nusse for reagents. The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EBI Data Bank with accession number(s) AY864332. This work was supported by National Institutes of Health Grant P20 RR018789 (to J.K.Y.) and by the State of Maine (to J.K.Y.). 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.
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NIHP20 RR018789
Issue or Number:19
Record Number:CaltechAUTHORS:NAMjbc06
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:5788
Deposited By: Archive Administrator
Deposited On:02 Nov 2006
Last Modified:08 Nov 2021 20:28

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