COUPLING OF THE C-CBL PROTOONCOGENE PRODUCT TO ERBB-1 EGF-RECEPTOR BUT NOT TO OTHER ERBB PROTEINS/

The ErbB family of transmembrane tyrosine kinases includes the recepto r for EGF (ErbB-1), two receptors for NDF/heregulin (ErbB-3 and ErbB-4 ) and an orphan receptor (ErbB-2). In order to examine the possibility that distinct signal transduction pathways are coupled to each ErbB p rotein, we examined the interaction of individual ligand-stimulated re ceptors with the c-Cbl protein, a protooncogene-encoded signaling mole cule previously identified in hematopoietic cells. We report that c-Cb l undergoes rapid and sustained phosphorylation on tyrosine residues u pon stimulation of fibroblast and epithelial cell lines with ligands o f ErbB-1. By contrast, activation of either ErbB-3 or ErbB-4 by NDF di d not affect tyrosine phosphorylation of c-Cbl. Likewise, activation o f a chimeric ligand-stimulatable ErbB-2 by a heterologous ligand was i neffective. Despite rapidity of the EGF effect, we observed no associa tion of c-Cbl with activated ErbB-1, implying that the interaction is indirect. Our in vitro experiments suggest that a candidate mediator o f the interaction is the Grb-2/Ash adaptor protein, which is constitut ively bound to c-Cbl. These results indicate that different ErbB prote ins can couple to distinct signaling pathways, and therefore their phy siological functions are probably non-redundant.