Wa5 is a novel ENU-induced antimorphic allele of the epidermal growth factor receptor
Wa5 is a novel ENU-induced antimorphic allele of the epidermal growth factor receptor
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DOI：
10.1007/s00335-004-2384-2
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发表时间：
2004-07-01
期刊：
影响因子：
2.5
通讯作者：
Threadgill, DW
中科院分区：
文献类型：
--
作者：
Lee, D;Cross, SH;Threadgill, DW
n -乙基-n -亚硝基源诱导的wave -5 （Wa5）突变的杂合小鼠，在显性、可见突变的筛选中分离出来，表现出与隐性Tgfa（wa1）或Egfr（wa2）等位基因的纯合小鼠相似的波浪状外壳。在这项研究中，我们发现Wa5是Egfr的一个新的等位基因（Egfr(Wa5)），在酪氨酸激酶结构域高度保守的DFG基序的编码区含有一个错义突变。胎盘发育、Apc（Min）肿瘤发生的修饰以及egf依赖性EGFR磷酸化水平的体内分析表明，EGFR （Wa5）作为一种抗同形等位基因发挥作用，再现了许多与EGFR活性降低相关的异常。此外，Egfr（wa5）增强Egfr（Wa2）化合物或Tgfa（tm1Dcl）双突变体，暴露额外的Egfr依赖表型。体外表征表明，Egfr（Wa5）的抗同形性是由激酶死亡受体作为显性阴性引起的。
Mice heterozygous for the N-ethyl-N-nitrosourea-induced Waved-5 (Wa5) mutation, isolated in a screen for dominant, visible mutations, exhibit a wavy coat similar to mice homozygous for the recessive Tgfa(wa1) or Egfr(wa2) alleles. in this study, we show that Wa5 is a new allele of Egfr (Egfr(Wa5)) containing a missense mutation within the coding region for the highly conserved DFG motif of the tyrosine kinase domain. In vivo analysis of placental development, modification of Apc(Min) tumorigenesis, and levels of EGF-dependent EGFR phosphorylation demonstrates that Egfr(Wa5) functions as an antimorphic allele, recapitulating many abnormalities associated with reduced EGFR activity. Furthermore, Egfr(wa5) enhances Egfr(Wa2) compound or Tgfa(tm1Dcl) double mutants exposing additional EGFR-dependent phenotypes. In vitro characterization shows that the antimorphic property of Egfr(Wa5) is caused by a kinase-dead receptor acting as a dominant negative.