TYROSINE PHOSPHORYLATION OF THE C-CBL PROTOONCOGENE PROTEIN PRODUCT AND ASSOCIATION WITH EPIDERMAL GROWTH-FACTOR (EGF) RECEPTOR UPON EGF STIMULATION

The murine retroviral oncogene v-cbl induces pre-B cell lymphomas and myelogenous leukemias. The protein product of the mammalian c-cbl proto-oncogene is a widely expressed cytoplasmic 120-kDa protein (p120(cbl)) whose normal cellular function has not been deter mined. Here we show that upon stimulation of human epidermal growth factor (EGF) receptor, p120(cbl) becomes strongly tyrosine-phosphorylated and associates with activated EGF receptor in vivo. A GST fusion protein containing amino acids 1-486 of p120(cbl), including a region highly conserved in nematodes, binds directly to the autophosphorylated carboxyl-terminal tail of the EGF receptor. Platelet derived growth factor (PDGF), fibroblast growth factor (FGF), or nerve growth factor (NGF) stimulation also results in tyrosine phosphorylation of p120(cbl). Recent genetic studies in Caenorhabditis elegans indicate that Sli-1, a p120(cbl) homologue, plays a negative regulatory role in control of the Ras signaling pathway initiated by the C. elegans EGF receptor homologue. Our results indicate that p120(cbl) is involved in an early step in the EGF signaling pathway that is conserved from nematodes to mammals.