THE HUMAN GRB2 AND DROSOPHILA-DRK GENES CAN FUNCTIONALLY REPLACE THE CAENORHABDITIS-ELEGANS CELL SIGNALING GENE SEM-5

Mutations in the Caenorhabditis elegans gene sem-5 affect cell signali ng processes involved in guiding a class of cell migrations and induci ng vulval cell fates. The sem-5 sequence encodes a protein comprised a lmost exclusively of SH2 and SH3 domains (SH, src homology region) tha t are found together in many signaling proteins and nonreceptor tyrosi ne kinases. A human protein, GRB2, was identified by its ability to as sociate with the activated human epidermal growth factor receptor (hEG FR). The GRB2 and Sem-5 proteins share an identical architecture of th eir SH2 and SH3 domains and 58% amino acid sequence identity. Here we demonstrate that GRB2 and a Drosophila sem-5-like gene Drk can specifi cally rescue sem-5 mutants. We also show that Sem-5, like GRB2, can bi nd to the activated hEGFR in vitro. We further correlate the abilities of several mutant variants of GRB2 and Sem-5 to bind to the hEGFR in vitro with their abilities to functionally replace sem-5 in vivo. Thes e data indicate that GRB2 and Drk are functional homologues of Sem-5 a nd demonstrate the high degree of conservation of both structure and f unction between signaling systems throughout evolution.