title: Wnt proteins synergize to activate β-catenin signaling.
abstract: Wnt ligands are involved in diverse signaling pathways that are active during development, maintenance of tissue homeostasis and in various disease states. While signaling regulated by individual Wnts has been extensively studied, Wnts are rarely expressed alone, and the consequences of Wnt gene co-expression are not well understood. Here, we studied the effect of co-expression of Wnts on the β-catenin signaling pathway. While some Wnts are deemed 'non-canonical' due to their limited ability to activate β-catenin when expressed alone, unexpectedly, we find that multiple Wnt combinations can synergistically activate β-catenin signaling in multiple cell types. WNT1- and WNT7B-mediated synergistic Wnt signaling requires FZD5, FZD8 and LRP6, as well as the WNT7B co-receptors GPR124 (also known as ADGRA2) and RECK. Unexpectedly, this synergistic signaling occurs downstream of β-catenin stabilization, and is correlated with increased lysine acetylation of β-catenin. Wnt synergy provides a general mechanism to confer increased combinatorial control over this important regulatory pathway.
authors.affiliation: Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore.
authors.forename: Anshula
authors.identifier: 0000-0002-1208-9116
authors.initials: A
authors.lastname: Alok
authors.affiliation: Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore.|Centre for Computational Biology, Duke-NUS Medical School, 169857 Singapore.
authors.forename: Zhengdeng
authors.identifier: 0000-0002-8938-6944
authors.initials: Z
authors.lastname: Lei
authors.affiliation: Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore.|Centre for Computational Biology, Duke-NUS Medical School, 169857 Singapore.
authors.forename: N Suhas
authors.identifier: 0000-0002-1857-8789
authors.initials: NS
authors.lastname: Jagannathan
authors.affiliation: Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore.
authors.forename: Simran
authors.identifier: 0000-0003-1510-928X
authors.initials: S
authors.lastname: Kaur
authors.affiliation: Centre for Computational Biology, Duke-NUS Medical School, 169857 Singapore.
authors.forename: Nathan
authors.identifier: 0000-0002-8589-2938
authors.initials: N
authors.lastname: Harmston
authors.affiliation: Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore.|Centre for Computational Biology, Duke-NUS Medical School, 169857 Singapore.
authors.forename: Steven G
authors.identifier: 0000-0002-4288-0056
authors.initials: SG
authors.lastname: Rozen
authors.affiliation: Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore.|Centre for Computational Biology, Duke-NUS Medical School, 169857 Singapore.
authors.forename: Lisa
authors.identifier: 0000-0002-1301-7069
authors.initials: L
authors.lastname: Tucker-Kellogg
authors.affiliation: Programme in Cancer and Stem Cell Biology, Duke-NUS Medical School, 169857 Singapore david.virshup@duke-nus.edu.sg.|Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.
authors.forename: David M
authors.identifier: 0000-0001-6976-850X
authors.initials: DM
authors.lastname: Virshup
mesh_terms: D000107:Acetylation; D002999:Clone Cells; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D055550:Protein Stability; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C531101:ADGRA2 protein, human; C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D051176:beta Catenin
keywords: Cancer; Development; GPCR; Synergy; Wnt signaling