EGF receptor function is required in late G(1) for cell cycle progression induced by bombesin and bradykinin

We examined the role of epidermal growth factor (EGF) receptor (EGFR) tyros ine kinase activation in G protein-coupled receptor (GPCR) agonist-induced mitogenesis in Swiss 3T3 and Rat-1 cells. Addition of EGFR tyrosine kinase inhibitors (e.g., tyrphostin AG-1478) abrogated bombesin-induced extracellu lar signal-regulated kinase (ERK) activation in Rat-1 cells but not in Swis s 3T3 cells, indicating the importance of cell context in determining the r ole of EGFR in ERK activation. In striking contrast, treatment with tyrphos tin AG-1478 markedly (similar to 70%) inhibited DNA synthesis induced by bo mbesin in both Swiss 3T3 and Rat-1 cells. Similar inhibition of bombesin-in duced DNA synthesis in Swiss 3T3 cells was obtained using four structurally different inhibitors of EGFR tyrosine kinase. Furthermore, kinetic analysi s indicates that EGFR function is necessary for bombesin-induced mitogenesi s in mid-late G(1) in both Swiss 3T3 and Rat-1 cells. Our results indicate that EGFR kinase activity is necessary in mid-late G(1) for promoting the a ccumulation of cyclins D1 and E and implicate EGFR function in the coupling of GPCR signaling to the activation of the cell cycle.