Rheb interacts with Raf-1 kinase and may function to integrate growth factor- and protein kinase A-dependent signals.
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.
Yee
W M
WM
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Worley
P F
PF
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001216:Asparagine / Q000378:metabolism; D002460:Cell Line; D005576:Colforsin; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism* / Q000502:physiology; D006133:Growth Substances / Q000494:pharmacology*; D048369:MAP Kinase Kinase 1; D048728:MAP Kinase Kinase Kinase 1; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins; D009414:Nerve Growth Factors / Q000494:pharmacology; D016501:Neurites; D009479:Neuropeptides / Q000378:metabolism* / Q000502:physiology; D015689:Oncogene Protein p21(ras) / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D011485:Protein Binding; 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; D000076205:Ras Homolog Enriched in Brain Protein; D051381:Rats; D011994:Recombinant Proteins; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D006133:Growth Substances; D009414:Nerve Growth Factors; D009479:Neuropeptides; D011518:Proto-Oncogene Proteins; D000076205:Ras Homolog Enriched in Brain Protein; D011994:Recombinant Proteins; C490213:Rheb protein, mouse; C087693:Rheb protein, rat; D005576:Colforsin; D012694:Serine; D004815:Epidermal Growth Factor; D001216:Asparagine; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482578:Map3k1 protein, mouse; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; D019204:GTP-Binding Proteins; D020559:Monomeric GTP-Binding Proteins; D015689:Oncogene Protein p21(ras)