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) tyrosine 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 extracellular signal-regulated kinase (ERK) activation in Rat-1 cells but not in Swiss 3T3 cells, indicating the importance of cell context in determining the role of EGFR in ERK activation. In striking contrast, treatment with tyrphostin AG-1478 markedly (~70%) inhibited DNA synthesis induced by bombesin in both Swiss 3T3 and Rat-1 cells. Similar inhibition of bombesin-induced DNA synthesis in Swiss 3T3 cells was obtained using four structurally different inhibitors of EGFR tyrosine kinase. Furthermore, kinetic analysis indicates that EGFR function is necessary for bombesin-induced mitogenesis 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 accumulation of cyclins D1 and E and implicate EGFR function in the coupling of GPCR signaling to the activation of the cell cycle.
Santiskulvong
C
C
Department of Medicine, School of Medicine and Molecular Biology Institute, University of California, Los Angeles, California 90095-1786, USA.
Sinnett-Smith
J
J
Rozengurt
E
E
D016475:3T3 Cells; D000818:Animals; D001839:Bombesin / Q000494:pharmacology*; D001920:Bradykinin / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology*; D016193:G1 Phase; D007700:Kinetics; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011799:Quinazolines; D051381:Rats; D018004:Receptors, Bombesin / Q000235:genetics / Q000502:physiology; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D020032:Tyrphostins / Q000494:pharmacology
D019927:Cyclin E; D004791:Enzyme Inhibitors; D011799:Quinazolines; D018004:Receptors, Bombesin; D011994:Recombinant Proteins; D020032:Tyrphostins; D019938:Cyclin D1; C101044:RTKI cpd; D004247:DNA; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D001839:Bombesin; D001920:Bradykinin