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.
Lee
Daekee
D
Department of Genetics, University of North Carolina School of Medicine, CB#7264, Chapel Hill, North Carolina, 27599, USA.
Cross
Sally H
SH
Strunk
Karen E
KE
Morgan
Joanne E
JE
Bailey
Candice L
CL
Jackson
Ian J
IJ
Threadgill
David W
DW
D000477:Alkylating Agents / Q000494:pharmacology; D000483:Alleles; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D006224:Cricetinae; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000235:genetics*; D005038:Ethylnitrosourea; D005799:Genes, Dominant; D005816:Genetic Complementation Test; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009153:Mutagens; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D017354:Point Mutation; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014162:Transfection
D000477:Alkylating Agents; D009153:Mutagens; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D005038:Ethylnitrosourea