We and others have shown that Cbl, the protein product of the c-cbl proto-oncogene, is an early target of tyrosine phosphorylation upon stimulation through the immune cell surface receptors, which signal through noncovalently associated cytoplasmic tyrosine kinases. Using human mammary epithelial cells that express a natural epidermal growth factor (EGF) receptor and require EGF as an essential growth factor, we demonstrate here that Cbl is a prominent target of tyrosine phosphorylation upon

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... mulation through the EGF receptor tyrosine kinase. Phosphorylation of Cbl was EGF dose-dependent, rapid (detectable as early as 5 s and maximal by 2 min), and relatively sustained (detectable even after 1 h). Co-immunoprecipitation studies demonstrated that Cbl became associated with the EGF receptor in an EGF-dependent manner. Cbl was basally associated with the adaptor protein growth factor receptorbinding protein 2 (Grb2), and this interaction was further enhanced by EGF stimulation; however, the interaction was entirely mediated via the Grb2