Differential Activation of ERK and JNK Mitogen-Activated Protein Kinases by Raf-1 and MEKK

• Published in: Science (American Association for the Advancement of Science) 1994-12, Vol.266 (5191), p.1719-1723
• Main Authors: Minden, Audrey, Lin, Anning, McMahon, Martin, Lange-Carter, Carol, Dérijard, Benoit, Davis, Roger J., Johnson, Gary L., Karin, Michael
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antigen antibody complex; Biochemistry; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell cycle, cell proliferation; Cell extracts; Cell growth; Cell physiology; COS cells; DNA; Enzyme Activation - drug effects; Epidermal Growth Factor - pharmacology; Extracellular signal-related kinases; Fundamental and applied biological sciences. Psychology; Genes, ras; Genetic vectors; Growth factors; HeLa Cells; Humans; Inhibition; JNK Mitogen-Activated Protein Kinases; Kinetics; Logical Thinking; MAP Kinase Kinase Kinase 1; Mice; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinases; Molecular and cellular biology; Nerve Growth Factors - pharmacology; PC12 Cells; Phosphorylation; Physiological aspects; Protein kinases; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-raf; ras Proteins - pharmacology; Rats; Receptors; Transfection; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.7992057

Growth factors activate mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinases (ERKs) and Jun kinases (JNKs). Although the signaling cascade from growth factor receptors to ERKs is relatively well understood, the pathway leading to JNK activation is more obscure. Activation of JNK by epidermal growth factor (EGF) or nerve growth factor (NGF) was dependent on H-Ras activation, whereas JNK activation by tumor necrosis factor α (TNF-α) was Ras-independent. Ras activates two protein kinases, Raf-1 and MEK (MAPK, or ERK, kinase) kinase (MEKK). Raf-1 contributes directly to ERK activation but not to JNK activation, whereas MEKK participated in JNK activation but caused ERK activation only after overexpression. These results demonstrate the existence of two distinct Ras-dependent MAPK cascades-one initiated by Raf-1 leading to ERK activation, and the other initiated by MEKK leading to JNK activation.