Abstract
Activation of mitogen-activated protein (MAP) kinase (also known as extracellular-signal-regulated kinase, or ERK) by growth factors can trigger either cell growth or differentiation. The intracellular signals that couple growth factors to MAP kinase may determine the different effects of growth factors: for example, transient activation of MAP kinase by epidermal growth factor stimulates proliferation of PC12 cells, whereas they differentiate in response to nerve growth factor, which acts partly by inducing a sustained activation of MAP kinase. Here we show that activation of MAP kinase by nerve growth factor involves two distinct pathways: the initial activation of MAP kinase requires the small G protein Ras, but its activation is sustained by the small G protein Rap1. Rap1 is activated by CRK adaptor proteins and the guanine-nucleotide-exchange factor C3G, and forms a stable complex with B-Raf, an activator of MAP kinase. Rap1 is required for at least two indices of neuronal differentiation by nerve growth factor: electrical excitability and the induction of neuron-specific genes. We propose that the activation of Rap1 by C3G represents a common mechanism to induce sustained activation of the MAP kinase cascade in cells that express B-Raf.
MeSH terms
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3T3 Cells
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Animals
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COS Cells
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Calcium-Calmodulin-Dependent Protein Kinases / genetics
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Differentiation
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DNA-Binding Proteins*
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Enzyme Activation
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Epidermal Growth Factor / metabolism
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GTP-Binding Proteins / genetics
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GTP-Binding Proteins / metabolism*
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Genes, Reporter
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Guanine Nucleotide Exchange Factors
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Guanosine Triphosphate / metabolism
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JNK Mitogen-Activated Protein Kinases*
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MAP Kinase Kinase 4
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Matrix Metalloproteinase 3 / genetics
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Matrix Metalloproteinase 3 / metabolism
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Mice
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase Kinases*
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Mutation
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Nerve Growth Factors / metabolism*
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Neurites / metabolism
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PC12 Cells
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Protein Kinases / metabolism
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Proteins / genetics
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Proteins / metabolism
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-crk
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Rats
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Transcription Factors*
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Transfection
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ets-Domain Protein Elk-1
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rap GTP-Binding Proteins
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ras Guanine Nucleotide Exchange Factors
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ras Proteins / metabolism
Substances
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Crk protein, rat
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DNA-Binding Proteins
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Elk1 protein, rat
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Guanine Nucleotide Exchange Factors
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Nerve Growth Factors
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Proteins
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-crk
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Transcription Factors
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ets-Domain Protein Elk-1
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ras Guanine Nucleotide Exchange Factors
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Epidermal Growth Factor
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Guanosine Triphosphate
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Protein Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase 1
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MAP Kinase Kinase 4
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Mitogen-Activated Protein Kinase Kinases
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Matrix Metalloproteinase 3
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GTP-Binding Proteins
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rap GTP-Binding Proteins
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ras Proteins