Lee Daekee, Cross Sally H, Strunk Karen E, Morgan Joanne E, Bailey Candice L, Jackson Ian J, Threadgill David W
Department of Genetics, University of North Carolina School of Medicine, CB#7264, Chapel Hill, North Carolina, 27599, USA.
Mamm Genome. 2004 Jul;15(7):525-36. doi: 10.1007/s00335-004-2384-2.
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.
在一项针对显性可见突变的筛选中分离出的、对N-乙基-N-亚硝基脲诱导的Waved-5（Wa5）突变呈杂合状态的小鼠，表现出与隐性Tgfa wa1或Egfr wa2等位基因纯合的小鼠相似的波浪状被毛。在本研究中，我们表明Wa5是Egfr的一个新等位基因（Egfr Wa5），在酪氨酸激酶结构域高度保守的DFG基序的编码区域内含有一个错义突变。对胎盘发育的体内分析、Apc Min肿瘤发生的改变以及EGF依赖的EGFR磷酸化水平表明，Egfr Wa5作为一个反效等位基因发挥作用，概括了许多与EGFR活性降低相关的异常情况。此外，Egfr wa5增强了Egfr Wa2复合突变体或Tgfa tm1Dcl双突变体，暴露了额外的EGFR依赖表型。体外特性表明，Egfr Wa5的反效特性是由作为显性负性的激酶失活受体引起的。
