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Ding, Y, Xi, Y, Chen, T, Wang, JY, Tao, DL, Wu, ZL, Li, YP, Li, C, Zeng, R and Li, L (2008) Caprin-2 enhances canonical Wnt signaling through regulating LRP5/6 phosphorylation. J. Cell Biol. 182:865-72
The low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) are coreceptors for Frizzled and transmit signals from the plasma membrane to the cytosol. However, the mechanism for LRP5/6 signal transmission remains undefined. Here, we identify cytoplasmic activation/proliferation-associated protein 2 (Caprin-2) as a LRP5/6-binding protein. Our data show that Caprin-2 stabilizes cytosolic beta-catenin and enhances lymphoid enhancer-binding factor 1/T cell factor-dependent reporter gene activity as well as the expression of Wnt target genes in mammalian cells. Morpholino-mediated knockdown of Caprin-2 in zebrafish embryos inhibits Wnt/beta-catenin signaling and results in a dorsalized phenotype. Moreover, Caprin-2 facilitates LRP5/6 phosphorylation by glycogen synthase kinase 3, and thus enhances the interaction between Axin and LRP5/6. Therefore, Caprin-2 promotes activation of the canonical Wnt signaling pathway by regulating LRP5/6 phosphorylation.
Animals; Axin Protein; Cell Cycle Proteins/genetics; Cell Cycle Proteins/physiology; Cell Line; Cytoplasm/metabolism; Embryo, Nonmammalian/anatomy & histology; Embryo, Nonmammalian/metabolism; Gene Expression Regulation; Gene Silencing; Glycogen Synthase Kinase 3/metabolism; Humans; LDL-Receptor Related Proteins/metabolism; Low Density Lipoprotein Receptor-Related Protein-5; Low Density Lipoprotein Receptor-Related Protein-6; Lymphoid Enhancer-Binding Factor 1/genetics; Lymphoid Enhancer-Binding Factor 1/metabolism; Phenotype; Phosphorylation; Repressor Proteins/metabolism; Signal Transduction; TCF Transcription Factors/genetics; TCF Transcription Factors/metabolism; Transcription, Genetic; Wnt Proteins/genetics; Wnt Proteins/metabolism; Zebrafish/embryology; Zebrafish/metabolism; beta Catenin/metabolism
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