Ras-Dependent Growth Factor Regulation of MEK Kinase in PC12 Cells

• Published in: Science (American Association for the Advancement of Science) 1994-09, Vol.265 (5177), p.1458-1461
• Main Authors: Lange-Carter, Carol A., Johnson, Gary L.
• Format: Article
• Language: English
• Subjects: Adipocytes; Animals; Antibodies; Antiserum; Biological and medical sciences; Cell growth; Cell lines; Cell physiology; Cyclic AMP - metabolism; Enzyme Activation; Epidermal Growth Factor - pharmacology; Fundamental and applied biological sciences. Psychology; Genes, ras; Growth factors; Immunoblotting; MAP Kinase Kinase 1; Mitogen-Activated Protein Kinase Kinases; Molecular and cellular biology; Nerve Growth Factors - pharmacology; PC12 Cells; Phosphorylation; Physiological regulation; Protein kinases; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-raf; Rats; Signal transduction; Tetradecanoylphorbol Acetate - pharmacology; Yeasts
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.8073291

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 N$^{17}$Ras. 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.