c‐Cbl Is Inducibly Tyrosine‐phosphorylated by Epidermal Growth Factor Stimulation in Fibroblasts, and Constitutively Tyrosine‐phosphorylated and Associated with v‐Src in v‐src‐transformed Fibroblasts

The c‐cbl gene was cloned as the cellular homolog of the v‐cbl oncogene that is the transforming component of a marine tumorigenic retrovirus, CAS NS‐1, though the biological roles of c‐Cbl remain to be elucidated. We have previously reported that c‐Cbl is implicated in the signal transduction triggered by granulocyte‐macrophage colony‐stimulating factor or erythropoietin in hematopoietic cells. Here, we observed tyrosine phosphorylation of c‐Cbl in cells expressing epidermal growth factor receptor depending on EGF stimulation and in v‐src transformed cells. Furthermore, c‐Cbl was revealed to associate with v‐Src in vivo. By means of binding experiments using glutathione S‐transferase fusion proteins, we have found that the SH2 and SH3 domains of many proteins bind to c‐Cbl. These findings strongly suggest that c‐Cbl is implicated in a wide variety of signal transduction pathways, including those of EGF receptor and Src protein, as well as in the signaling pathways of hematopoietic cells.