Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization
Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization
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DOI：
10.1038/ncb1081
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发表时间：
2004-01-01
影响因子：
21.3
通讯作者：
Moon, RT
中科院分区：
文献类型：
--
作者：
Kaykas, A;Yang-Snyder, J;Moon, RT
Nt信号通路调节细胞增殖、细胞命运和形态发生运动。在这里，我们证明了Wnt受体的Frizzled （Fz）家族（1-4），类似于g蛋白偶联受体（gpcr）（5-7），形成特异性的同源和异聚物。两种证据表明，寡聚化发生在内质网中：首先，Fz4的突变等位基因编码保留在内质网中的截断蛋白，与常染色体显性视网膜退行性疾病家族性渗出性玻璃体视网膜病变（FEVR）有关(8)。我们发现这种突变形式的Fz4与野生型Fz4寡聚，将其保留在内质网中并抑制其信号传导。其次，针对内质网的Fz1衍生物将野生型Fz1困在内质网中并阻断其信号传导。这些数据支持突变型和野生型Fz蛋白在内质网发生寡聚化的假设，并可能解释该FEVR等位基因的遗传优势。
nt signalling pathways regulate cell proliferation, cell fate and morphogenetic movements. Here, we demonstrate that the Frizzled (Fz) family of Wnt receptors(1-4), similarly to G-protein-coupled receptors (GPCRs)(5-7), 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.