title: R-Spondin1 regulates Wnt signaling by inhibiting internalization of LRP6.
abstract: The R-Spondin (RSpo) family of secreted proteins act as potent activators of the Wnt/beta-catenin signaling pathway. We have previously shown that RSpo proteins can induce proliferative effects on the gastrointestinal epithelium in mice. Here we provide a mechanism whereby RSpo1 regulates cellular responsiveness to Wnt ligands by modulating the cell-surface levels of the coreceptor LRP6. We show that RSpo1 activity critically depends on the presence of canonical Wnt ligands and LRP6. Although RSpo1 does not directly activate LRP6, it interferes with DKK1/Kremen-mediated internalization of LRP6 through an interaction with Kremen, resulting in increased LRP6 levels on the cell surface. Our results support a model in which RSpo1 relieves the inhibition DKK1 imposes on the Wnt pathway.
authors.affiliation: Nuvelo, Inc., 201 Industrial Road, Suite 310, San Carlos, CA 94070-6211, USA.
authors.forename: Minke E
authors.initials: ME
authors.lastname: Binnerts
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Kim
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Bright
authors.forename: Sejal M
authors.initials: SM
authors.lastname: Patel
authors.forename: Karolyn
authors.initials: K
authors.lastname: Tran
authors.forename: Mei
authors.initials: M
authors.lastname: Zhou
authors.forename: John M
authors.initials: JM
authors.lastname: Leung
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Woodrow E
authors.initials: WE
authors.lastname: Lomas
authors.forename: Melissa
authors.initials: M
authors.lastname: Dixon
authors.forename: Sophie A
authors.initials: SA
authors.lastname: Hazell
authors.forename: Marie
authors.initials: M
authors.lastname: Wagle
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Nie
authors.forename: Nenad
authors.initials: N
authors.lastname: Tomasevic
authors.forename: Jason
authors.initials: J
authors.lastname: Williams
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhan
authors.forename: Michael D
authors.initials: MD
authors.lastname: Levy
authors.forename: Walter D
authors.initials: WD
authors.lastname: Funk
authors.forename: Arie
authors.initials: A
authors.lastname: Abo
mesh_terms: D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000166:cytology; D026502:LDL-Receptor Related Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008156:Luciferases / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation; D011233:Precipitin Tests; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D019699:Thrombospondins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D000098907:R-Spondins