TYROSINE PHOSPHORYLATION OF BCR BY FPS FES PROTEIN-TYROSINE KINASES INDUCES ASSOCIATION OF BCR WITH GRB-2/SOS/

The human bcr gene encodes a protein with serine/threonine kinase acti vity, CDC24/dbl homology, a GAP domain, and an SH2-binding region. How ever, the precise physiological functions of BCR are unknown. Coexpres sion of BCR with the cytoplasmic protein-tyrosine kinase encoded by th e c-fes proto-oncogene in Sf-9 cells resulted in stable BCR-FES protei n complex formation and tyrosine phosphorylation of BCR Association in volves the SH2 domain of FES and a novel binding domain localized to t he first 347 amino acids of the FES N-terminal region. Deletion of the homologous N-terminal BCR-binding domain from v-fps, a fes-related tr ansforming oncogene, abolished transforming activity and tyrosine phos phorylation of BCR in vivo. Tyrosine phosphorylation of BCR in v-fps-t ransformed cells induced its association with GRB-2/SOS, the RAS guani ne nucleotide exchange factor complex. These data provide evidence tha t BCR couples the cytoplasmic protein-tyrosine kinase and RAS signalin g pathways.