Reduced ability of transforming growth factor-alpha to induce EGF receptor heterodimerization and downregulation suggests a mechanism of oncogenic synergy with ErbB2

The epidermal growth factor receptor (EGFR) is activated by a variety of ligands including EGF and transforming growth factor-alpha (TGF alpha), whereas no ligand for the homologous ErbB2 oncoprotein has yet been identified. Here we use both an ErbB2 phosphoantibody (aPY(1222)) and an activation-specific EGFR antibody to show that low concentrations of EGF induce more efficient tyrosine phosphorylation of ErbB2 in A431 cells than does equimolar TGF alpha, while EGFR is more potently activated by TGF alpha. Co-precipitation studies confirm that heterodimerization of activated EGFR and transphosphorylated ErbB2 is readily induced by EGF but not TGF alpha. ECFR downregulation is also more efficiently induced by EGF, suggesting that ligand-dependent modification of ErbB2 may be required to terminate EGFR signalling in cells expressing both receptor types. These findings indicate that EGF and TGF alpha differ in their abilities to induce tyrosine phosphorylation and heterodimerization of ErbB2, and raise the possibility that ErbB2 exerts its oncogenic effect in part by impairing TGF alpha-dependent EGFR downregulation.