title: EGF receptor function is required in late G(1) for cell cycle progression induced by bombesin and bradykinin.
abstract: 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.
authors.affiliation: Department of Medicine, School of Medicine and Molecular Biology Institute, University of California, Los Angeles, California 90095-1786, USA.
authors.forename: C
authors.initials: C
authors.lastname: Santiskulvong
authors.forename: J
authors.initials: J
authors.lastname: Sinnett-Smith
authors.forename: E
authors.initials: E
authors.lastname: Rozengurt
mesh_terms: 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
chemical_list: 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