A DROSOPHILA SH2-SH3 ADAPTER PROTEIN IMPLICATED IN COUPLING THE SEVENLESS TYROSINE KINASE TO AN ACTIVATOR OF RAS GUANINE-NUCLEOTIDE EXCHANGE, SOS

A Drosophila gene (drk) encodes a widely expressed protein with a single SH2 domain and two flanking SH3 domains, which is homologous to the Sem-5 protein of C. elegans and mammalian GRB2. Genetic analysis suggests that drk function is essential for signaling by the sevenless receptor tyrosine kinase. Drk biological activity correlates with binding of its SH2 domain to activated receptor tyrosine kinases and concomitant localization of drk to the plasma membrane. In vitro, drk also binds directly to the C-terminal tail of Sos, a Ras guanine nucleotide-releasing protein (GNRP), which, like Ras1 and drk, is required for sevenless signaling. These results suggest that drk binds autophosphorylated receptor tyrosine kinases with its SH2 domain and the Sos GNRP through its SH3 domains, thereby coupling receptor tyrosine kinases to Ras activation. The conservation of these signaling proteins during evolution indicates that this is a general mechanism for linking tyrosine kinases to Ras.