title: Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization.
abstract: nt signalling pathways regulate cell proliferation, cell fate and morphogenetic movements. Here, we demonstrate that the Frizzled (Fz) family of Wnt receptors, similarly to G-protein-coupled receptors (GPCRs), form specific homo- and hetero-oligomers. Two lines of evidence suggest that oligomerization occurs in the endoplasmic reticulum: first, a mutant allele of Fz4, encoding a truncated protein that is retained in the endoplasmic reticulum, is linked to the autosomal-dominant retinal degenerative disease, familial exudative vitreoretinopathy (FEVR). We show that this mutant form of Fz4 oligomerizes with wild-type Fz4, retains it in the endoplasmic reticulum and inhibits its signalling. Second, a derivative of Fz1 targeted to the endoplasmic reticulum traps wild-type Fz1 in the endoplasmic reticulum and blocks its signalling. These data support the hypothesis that oligomerization of mutant and wild-type Fz proteins occurs in the endoplasmic reticulum and may explain the genetic dominance of this FEVR allele.
authors.affiliation: Howard Hughes Medical Institute, Department of Pharmacology, and Center for Developmental Biology, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Ajamete
authors.initials: A
authors.lastname: Kaykas
authors.forename: Julia
authors.initials: J
authors.lastname: Yang-Snyder
authors.forename: Madeleine
authors.initials: M
authors.lastname: Héroux
authors.forename: Kavita V
authors.initials: KV
authors.lastname: Shah
authors.forename: Michel
authors.initials: M
authors.lastname: Bouvier
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
mesh_terms: D000483:Alleles; D000818:Animals; D019556:COS Cells; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D051157:Frizzled Receptors; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D018630:Vitreoretinopathy, Proliferative / Q000235:genetics*; D051153:Wnt Proteins; D029961:Zebrafish Proteins
chemical_list: C489740:FZD1 protein, human; C402930:FZD4 protein, human; D051157:Frizzled Receptors; D010446:Peptide Fragments; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D051153:Wnt Proteins; D029961:Zebrafish Proteins