MUTATION OF PROLINE-1003 TO GLYCINE IN THE EPIDERMAL GROWTH-FACTOR (EGF) RECEPTOR ENHANCES RESPONSIVENESS TO EGF

We have shown previously that the epidermal growth factor (EGF) recept or is phosphorylated at Ser-1002 and that this phosphorylation is asso ciated with desensitization of the EGF receptor. Ser-1002 is followed immediately by Pro-1003, a residue that may promote the adoption of a specific conformation at this site or serve as a recognition element f or the interaction of the EGF receptor with other proteins. To examine these possibilities, we have mutated Pro-1003 of the EGF receptor to a Gly residue and have analyzed the effect of this mutation on EGF-sti mulated signaling. Cells expressing the P1003G EGF receptors exhibited higher EGF-stimulated autophosphorylation and synthetic peptide phosp horylation compared to cells expressing wild-type EGF receptors. In ad dition, the ability of EGF to stimulate PI 3-kinase activity and mitog en-activated protein kinase activity was enhanced in cells expressing the P1003G EGF receptor. Cells expressing P1003G receptors also demons trated an increased ability to form colonies in soft agar in response to EGF. These results indicate that mutation of Pro-1003 leads to a po tentiation of the biological effects of EGF. The findings are consiste nt with the hypothesis that Pro-1003 plays a role in a form of regulat ion that normally suppresses EGF receptor function.