title: Multi-functional norrin is a ligand for the LGR4 receptor.
abstract: Mammalian LGR4, 5 and 6 are seven-transmembrane receptors that are important for diverse physiological processes. These receptors are orthologous to DLGR2, a Drosophila receptor activated by the burs/pburs heterodimer important for morphogenesis. Although recent studies indicated that four R-spondin proteins are cognate ligands for LGR4, 5 and 6 receptors, several BMP antagonists in vertebrates have been postulated to be orthologous to burs and pburs. Using newly available genome sequences, we showed that norrin is a vertebrate ortholog for insect burs and pburs and stimulates Wnt signaling mediated by LGR4, but not by LGR5 and 6, in mammalian cells. Although norrin could only activate LGR4, binding studies suggested interactions between norrin and LGR4, 5 and 6. Norrin, the Norrie disease gene product, is also capable of activating Wnt signaling mediated by the Frizzled4 receptor and serves as a BMP antagonist. Mutagenesis studies indicated that different norrin mutations found in patients with Norrie disease can be categorized into subgroups according to defects for signaling through the three distinct binding proteins. Thus, norrin is a rare ligand capable of binding three receptors/binding proteins that are important for BMP and Wnt signaling pathways.
authors: Program of Reproductive and Stem Cell Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA 94305-5317, USA.
authors: Cheng
authors: C
authors: Deng
authors: Pradeep
authors: P
authors: Reddy
authors: Yuan
authors: Y
authors: Cheng
authors: Ching-Wei
authors: CW
authors: Luo
authors: Chih-Lun
authors: CL
authors: Hsiao
authors: Aaron J W
authors: AJ
authors: Hsueh
mesh_terms: D000818:Animals; D002645:Chickens; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology; D014981:Xenopus
chemical_list: D029721:Drosophila Proteins; D005136:Eye Proteins; C402930:FZD4 protein, human; D051157:Frizzled Receptors; C498581:Fzd4 protein, mouse; C411562:LGR4 protein, human; C496200:LGR4 protein, mouse; C081848:NDP protein, human; C489916:Ndph protein, mouse; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled
keywords: BMP antagonist; LGR4; Ligand–receptor interaction; Norrin; Wnt signaling