Abstract
Rheb is a recently described member of the Ras family that was originally identified as an immediate-early gene in brain but is also widely expressed in other tissues. Here we demonstrate that Rheb interacts with and appears to regulate Raf-1 kinase, an essential component of the H-Ras signaling pathway. In direct contrast to H-Ras, however, the interaction of Rheb with Raf-1 is potentiated by growth factors in combination with agents that increase cyclic AMP (cAMP) levels. Protein kinase A-dependent phosphorylation of serine 43 within the regulatory domain of Raf-1 reciprocally potentiates its interaction with Rheb and decreases its interaction with H-Ras. A single amino acid in the G2 effector domain is critical for the differential properties of Rheb. Since Rheb is an immediate-early gene, our studies suggest that Rheb functions in concert with H-Ras to dynamically integrate cAMP and growth factor signaling.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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3T3 Cells
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Amino Acid Sequence
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Animals
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Asparagine / metabolism
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Cell Line
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Colforsin
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Cyclic AMP / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Epidermal Growth Factor / pharmacology
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GTP-Binding Proteins / metabolism*
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GTP-Binding Proteins / physiology
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Growth Substances / pharmacology*
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MAP Kinase Kinase 1
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MAP Kinase Kinase Kinase 1*
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Mice
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Mitogen-Activated Protein Kinase Kinases*
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Molecular Sequence Data
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Monomeric GTP-Binding Proteins*
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Nerve Growth Factors / pharmacology
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Neurites
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Neuropeptides / metabolism*
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Neuropeptides / physiology
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Oncogene Protein p21(ras) / metabolism
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PC12 Cells
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Phosphorylation
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Protein Binding
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Protein Serine-Threonine Kinases / metabolism*
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-raf
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Ras Homolog Enriched in Brain Protein
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Rats
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Recombinant Proteins
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Serine / metabolism
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Signal Transduction / physiology*
Substances
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Growth Substances
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Nerve Growth Factors
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Neuropeptides
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Proto-Oncogene Proteins
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Ras Homolog Enriched in Brain Protein
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Recombinant Proteins
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Rheb protein, mouse
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Rheb protein, rat
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Colforsin
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Serine
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Epidermal Growth Factor
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Asparagine
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Cyclic AMP
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Cyclic AMP-Dependent Protein Kinases
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MAP Kinase Kinase Kinase 1
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Map3k1 protein, mouse
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MAP Kinase Kinase 1
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Map2k1 protein, mouse
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Mitogen-Activated Protein Kinase Kinases
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GTP-Binding Proteins
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Monomeric GTP-Binding Proteins
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Oncogene Protein p21(ras)