Ras-dependent growth factor regulation of MEK kinase in PC12 cells.
Mitogen-activated protein kinases (MAPKs) are rapidly activated in response to stimulation of diverse receptor types. MAPKs are positively regulated by phosphorylation on threonine and tyrosine by MAP kinase or extracellular signal-regulated kinase (ERK) kinases (MEKs). MEK kinase (MEKK) is part of a family of serine-threonine protein kinases that phosphorylate and activate MEKs independently of Raf. MEKK was rapidly and persistently activated in response to stimulation of resting PC12 cells with epidermal growth factor (EGF). Nerve growth factor (NGF) and 12-O-tetradecanoylphorbol-13-acetate (TPA) also activated MEKK, although to a lesser degree than did EGF. Activation of MEKK and B-Raf in response to EGF was inhibited by expression of dominant negative N17Ras. Expression of oncogenic Ras resulted in activation of MEKK. Stimulation of synthesis of cyclic adenosine 3',5'-monophosphate abolished activation of MEKK and B-Raf by EGF, NGF, and TPA. Thus, Ras simultaneously controls the activation of members of the Raf and MEKK families of protein kinases.
Lange-Carter
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CA
Division of Basic Sciences, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Johnson
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GL
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D011905:Genes, ras; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D009414:Nerve Growth Factors / Q000494:pharmacology*; D016716:PC12 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D013755:Tetradecanoylphorbol Acetate