EGF induces biphasic S6 kinase activation: late phase is protein kinase C-dependent and contributes to mitogenicity.
Detailed kinetics reveal that EGF-induced S6 kinase activation is biphasic: an early phase appears at 10-15 min, followed by a late phase between 30 and 60 min. Both activities exhibit the same chromatographic behavior and sensitivity to phosphatase 2A. Direct activation of protein kinase C by TPA induces only late phase activity. Down-regulation of protein kinase C leads to loss of both TPA- and EGF-induced late phase activity, while the early phase is unaffected. The loss of late phase kinase activity results in decreased EGF-induced S6 phosphorylation, protein synthesis, and cell growth. The results indicate that EGF differentially regulates S6 kinase activation by two distinct signaling pathways and that loss of the late or protein kinase C-dependent phase leads to a diminished mitogenic response.
Susa
M
M
Friedrich Miescher Institut, Basel, Switzerland.
Olivier
A R
AR
Fabbro
D
D
Thomas
G
G
D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008938:Mitosis / Q000187:drug effects*; D009132:Muscles / Q000201:enzymology / Q000502:physiology; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D011817:Rabbits; D019893:Ribosomal Protein S6 Kinases; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004815:Epidermal Growth Factor; D011494:Protein Kinases; D066246:ErbB Receptors; D019893:Ribosomal Protein S6 Kinases; D011493:Protein Kinase C; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D013755:Tetradecanoylphorbol Acetate