DIRECT AND SPECIFIC INTERACTION OF C-SRC WITH NEU IS INVOLVED IN SIGNALING BY THE EPIDERMAL GROWTH-FACTOR RECEPTOR

Transgenic mice expressing either the activated or wild type neu oncog ene heritably develop metastatic mammary tumors. Tumor development in this transgenic mouse model correlates with activation of the Neu tyro sine kinase. Recently, we have shown that these Neu-induced mammary tu mors possess elevated c-Src tyrosine kinase activity. Here, we demonst rate that c-Src requires tyrosine phosphorylated Neu for its ability t o associate with Neu in vivo and this association is likely the result of a direct physical binding of c-Src SH2 domain to the tyrosine phos phorylated Neu. By contrast, the c-Src SH2 domain did not interact dir ectly with tyrosine phosphorylated EGFR. Moreover, in established cell lines expressing elevated levels of EGFR, EGF stimulation results in transphosphorylation of Neu and formation of complexes between c-Src a nd tyrosine phosphorylated Neu. Taken together, these observations sug gest that activation of c-Src by these two closely related EGFR family members results from a direct and specific interaction of c-Src with tyrosine phosphorylated Neu.