Inhibition by cAMP of Ras-dependent activation of Raf.
Activation of the Raf and extracellular signal-regulated kinases (ERKs) (or mitogen-activated protein kinases) are key events in mitogenic signalling, but little is known about interactions with other signaling pathways. Agents that raise levels of intracellular cyclic adenosine 3',5'-monophosphate (cAMP) blocked DNA synthesis and signal transduction in Rat1 cells exposed to epidermal growth factor (EGF) or lysophosphatidic acid. In the case of EGF, receptor tyrosine kinase activity and association with the signaling molecules Grb2 and Shc were unaffected by cAMP. Likewise, EGF-dependent accumulation of the guanosine 5'-triphosphate-bound form of Ras was unaffected. In contrast, activation of Raf-1 and ERK kinases was inhibited. Thus, cAMP appears to inhibit signal transmission from Ras by preventing Ras-dependent activation of Raf-1.
Cook
S J
SJ
Onyx Pharmaceuticals, Richmond, CA 94806.
McCormick
F
F
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D007399:Interphase; D008246:Lysophospholipids / Q000494:pharmacology; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019908:Proto-Oncogene Proteins c-raf; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction
D008246:Lysophospholipids; D011518:Proto-Oncogene Proteins; D004815:Epidermal Growth Factor; D003994:Bucladesine; D002772:Cholera Toxin; D000242:Cyclic AMP; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D019908:Proto-Oncogene Proteins c-raf; D017868:Cyclic AMP-Dependent Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras); D015056:1-Methyl-3-isobutylxanthine