title: Syndecan-4 inhibits Wnt/β-catenin signaling through regulation of low-density-lipoprotein receptor-related protein (LRP6) and R-spondin 3.
abstract: Regulation of Wnt signaling is crucial for embryonic development and adult homeostasis. Here we study the role of Syndecan-4 (SDC4), a cell-surface heparan sulphate proteoglycan, and Fibronectin (FN), in Wnt/β-catenin signaling. Gain- and loss-of-function experiments in mammalian cell lines and Xenopus embryos demonstrate that SDC4 and FN inhibit Wnt/β-catenin signaling. Epistatic and biochemical experiments show that this inhibition occurs at the cell membrane level through regulation of LRP6. R-spondin 3, a ligand that promotes canonical and non-canonical Wnt signaling, is more prone to potentiate Wnt/β-catenin signaling when SDC4 levels are reduced, suggesting a model whereby SDC4 tunes the ability of R-spondin to modulate the different Wnt signaling pathways. Since SDC4 has been previously related to non-canonical Wnt signaling, our results also suggest that this proteoglycan can be a key component in the regulation of Wnt signaling.
authors.affiliation: Center for Aging and Regeneration, Millennium Nucleus in Regenerative Biology, Faculty of Biological Sciences, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Astudillo
authors.affiliation: Center for Aging and Regeneration, Millennium Nucleus in Regenerative Biology, Faculty of Biological Sciences, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile.
authors.forename: Héctor
authors.initials: H
authors.lastname: Carrasco
authors.affiliation: Center for Aging and Regeneration, Millennium Nucleus in Regenerative Biology, Faculty of Biological Sciences, P. Universidad Católica de Chile, Alameda 340, Santiago, Chile. Electronic address: jlarrain@bio.puc.cl.
authors.forename: Juan
authors.initials: J
authors.lastname: Larraín
mesh_terms: D000818:Animals; D018929:Cell Culture Techniques; D005353:Fibronectins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*; D000098907:R-Spondins
chemical_list: D005353:Fibronectins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D053671:Syndecan-4; D019699:Thrombospondins; D051176:beta Catenin; C555475:LRP6 protein, human; C555476:Lrp6 protein, mouse; C517523:R-spondin3 protein, mouse; C475438:RSPO3 protein, human; D000098907:R-Spondins
keywords: Fibronectin; LRP6; R-spondin; Syndecan-4; Wnt