Wa5 is a novel ENU-induced antimorphic allele of the epidermal growth factor receptor

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.