Our previous work indicates that structural determinants in the catalytic domain of the epidermal growth factor receptor (EGFR) and erbB-2 gpl85 account for the specificity of signal transduction of these two related but different receptors. The degree of sequence homology in the tyrosine kinase domain of these two receptors is about 80% at the amino acid level. However, discrete areas of sequence divergence can be found and they appear to be colinear with region of sequence divergence in related members of two other receptor subfamilies, i.e., the hIR/IGFI-R subfamily and c-kit/c-fms subfamily. It is, therefore, conceivable that these stretches of sequence divergence may account for specificity of signal transduction. To test this hypothesis, we have introduced mutations in these regions of the EGFR catalytic domain. One of these mutants contains a deletion between residues 660 and 667 (EGFR delta 660-667) and is similar to the wild type EGFR in its catalytic properties, as assessed in a variety of assays. Furthermore, this mutant EGFR binds EGF with the same affinity as its normal counterpart. However, when expressed into NR6 fibroblasts, the EGFR delta 660-667 mutant displays a 60% reduction of its EGF induced mitogenic activity. These results indicate that the region affected by the delta 660-667 deletion is involved in the recognition of cellular substrates of the EGFR. Current efforts are aimed at the biochemical characterization of proteins which are selectively phosphorylated by the wild type EGFR but not by the delta 660-667 mutant.
