R-Spondin Family Members Regulate the Wnt Pathway by a Common Mechanism
| Autor: | Wouter Korver, Xiaoming Zhan, Minke E. Binnerts, Shirlee Yonkovich, Shouchun Liu, Arie Abo, Melissa Dixon, Delphine Gros, Karolyn Tran, Marie Wagle, Kyung Ah Kim, Nenad Tomasevic |
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| Rok vydání: | 2008 |
| Předmět: |
Beta-catenin
Receptors Cell Surface Ligands TCF/LEF family Cell Line Mice Animals Humans RSPO1 Molecular Biology RSPO2 LDL-Receptor Related Proteins beta Catenin biology Wnt signaling pathway LRP6 LRP5 Articles Cell Biology Protein Structure Tertiary Cell biology Wnt Proteins DKK1 Low Density Lipoprotein Receptor-Related Protein-6 biology.protein Intercellular Signaling Peptides and Proteins TCF Transcription Factors Thrombospondins Signal Transduction |
| Zdroj: | Molecular Biology of the Cell. 19:2588-2596 |
| ISSN: | 1939-4586 1059-1524 |
| DOI: | 10.1091/mbc.e08-02-0187 |
| Popis: | The R-Spondin (RSpo) family of secreted proteins is implicated in the activation of the Wnt signaling pathway. Despite the high structural homology between the four members, expression patterns and phenotypes in knockout mice have demonstrated striking differences. Here we dissected and compared the molecular and cellular function of all RSpo family members. Although all four RSpo proteins activate the canonical Wnt pathway, RSpo2 and 3 are more potent than RSpo1, whereas RSpo4 is relatively inactive. All RSpo members require Wnt ligands and LRP6 for activity and amplify signaling of Wnt3A, Wnt1, and Wnt7A, suggesting that RSpo proteins are general regulators of canonical Wnt signaling. Like RSpo1, RSpo2-4 antagonize DKK1 activity by interfering with DKK1 mediated LRP6 and Kremen association. Analysis of RSpo deletion mutants indicates that the cysteine-rich furin domains are sufficient and essential for the amplification of Wnt signaling and inhibition of DKK1, suggesting that Wnt amplification by RSpo proteins may be a direct consequence of DKK1 inhibition. Together, these findings indicate that RSpo proteins modulate the Wnt pathway by a common mechanism and suggest that coexpression with specific Wnt ligands and DKK1 may determine their biological specificity in vivo. |
| Databáze: | OpenAIRE |
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