Cripto-1 enhances the canonical Wnt/β-catenin signaling pathway by binding to LRP5 and LRP6 co-receptors

• Published in: Cellular signalling 2013-01, Vol.25 (1), p.178-189
• Main Authors: Nagaoka, Tadahiro, Karasawa, Hideaki, Turbyville, Thomas, Rangel, Maria-Cristina, Castro, Nadia P., Gonzales, Monica, Baker, Alyson, Seno, Masaharu, Lockett, Stephen, Greer, Yoshimi E., Rubin, Jeffrey S., Salomon, David S., Bianco, Caterina
• Format: Article
• Language: English
• Subjects: Activation; Animals; beta Catenin - metabolism; Binding; Cell Line; Cell Movement; Cellular; Colon; Cripto-1; Embryos; Genes; GPI-Linked Proteins - chemistry; GPI-Linked Proteins - metabolism; HEK293 Cells; Humans; Intercellular Signaling Peptides and Proteins - chemistry; Intercellular Signaling Peptides and Proteins - metabolism; Low Density Lipoprotein Receptor-Related Protein-5 - genetics; Low Density Lipoprotein Receptor-Related Protein-5 - metabolism; Low Density Lipoprotein Receptor-Related Protein-6 - genetics; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism; LRP5; LRP6; Mice; Neoplasm Proteins - chemistry; Neoplasm Proteins - metabolism; Pathways; Protein Binding; Protein Structure, Tertiary; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Transcriptional Activation; Transformations; Wnt signaling; Wnt Signaling Pathway; Wnt3A Protein - metabolism; β-Catenin
• ISSN: 0898-6568; 1873-3913; 1873-3913
• DOI: 10.1016/j.cellsig.2012.09.024

Cripto-1 is implicated in multiple cellular events, including cell proliferation, motility and angiogenesis, through the activation of an intricate network of signaling pathways. A crosstalk between Cripto-1 and the canonical Wnt/β-catenin signaling pathway has been previously described. In fact, Cripto-1 is a downstream target gene of the canonical Wnt/β-catenin signaling pathway in the embryo and in colon cancer cells and T-cell factor (Tcf)/lymphoid enhancer factor binding sites have been identified in the promoter and the first intronic region of the mouse and human Cripto-1 genes. We now demonstrate that Cripto-1 modulates signaling through the canonical Wnt/β-catenin/Tcf pathway by binding to the Wnt co-receptors low-density lipoprotein receptor-related protein (LRP) 5 and LRP6, which facilitates Wnt3a binding to LRP5 and LRP6. Cripto-1 functionally enhances Wnt3a signaling through cytoplasmic stabilization of β-catenin and elevated β-catenin/Tcf transcriptional activation. Conversely, Wnt3a further increases Cripto-1 stimulation of migration, invasion and colony formation in soft agar of HC11 mouse mammary epithelial cells, indicating that Cripto-1 and the canonical Wnt/β-catenin signaling co-operate in regulating motility and in vitro transformation of mammary epithelial cells. ► Cripto-1 enhances the canonical Wnt/β-catenin signaling pathway. ► Cripto-1 binds to the Wnt co-receptors LRP5 and LRP6 on the cell surface. ► Cripto-1 induces cytoplasmic stabilization of β-catenin. ► Wnt3a enhances Cripto-1 stimulation of mammary epithelial cell motility and growth.