Letter abstract
Nature Cell Biology 6, 52 - 58 (2003)
Published online: 14 December 2003 | doi:10.1038/ncb1081
Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization
Ajamete Kaykas1, Julia Yang-Snyder1, Madeleine Héroux2, Kavita V. Shah1, Michel Bouvier2 & Randall T. Moon1
nt signalling pathways regulate cell proliferation, cell fate and morphogenetic movements. Here, we demonstrate that the Frizzled (Fz) family of Wnt receptors1, 2, 3, 4, similarly to G-protein-coupled receptors (GPCRs)5, 6, 7, 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)8. 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.
- Howard Hughes Medical Institute, Department of Pharmacology, and Center for Developmental Biology, University of Washington School of Medicine, Seattle, WA 98195, USA.
- Département de Biochimie, Université de Montréal, Montréal, Québec H3C 3J7, Canada.
Correspondence to: Randall T. Moon1 e-mail: rtmoon@u.washington.edu
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