title: Separate cyclic AMP sensors for neuritogenesis, growth arrest, and survival of neuroendocrine cells.
abstract: Dividing neuroendocrine cells differentiate into a neuronal-like phenotype in response to ligands activating G protein-coupled receptors, leading to the elevation of the second messenger cAMP. Growth factors that act at receptor tyrosine kinases, such as nerve growth factor, also cause differentiation. We report here that two aspects of cAMP-induced differentiation, neurite extension and growth arrest, are dissociable at the level of the sensors conveying the cAMP signal in PC12 and NS-1 cells. Following cAMP elevation, neuritogenic cyclic AMP sensor/Rapgef2 is activated for signaling to ERK to mediate neuritogenesis, whereas Epac2 is activated for signaling to the MAP kinase p38 to mediate growth arrest. Neither action of cAMP requires transactivation of TrkA, the receptor for NGF. In fact, the differentiating effects of NGF do not require activation of any of the cAMP sensors protein kinase A, Epac, or neuritogenic cyclic AMP sensor/Rapgef2 but, rather, depend on ERK and p38 activation via completely independent signaling pathways. Hence, cAMP- and NGF-dependent signaling for differentiation are also completely insulated from each other. Cyclic AMP and NGF also protect NS-1 cells from serum withdrawal-induced cell death, again by two wholly separate signaling mechanisms, PKA-dependent for cAMP and PKA-independent for NGF.
authors.affiliation: From the Section on Molecular Neuroscience and.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Emery
authors.forename: Maribeth V
authors.initials: MV
authors.lastname: Eiden
authors.forename: Lee E
authors.initials: LE
authors.lastname: Eiden
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000502:physiology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020932:Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D055099:Neuroendocrine Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D016716:PC12 Cells; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; C531571:Rapgef4 protein, rat; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D020917:Receptor, trkA; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Cyclic AMP (cAMP); ERK; Epac; Guanine Nucleotide Exchange Factor (GEF); NCS/Rapgef2; Protein Kinase A (PKA); p38 MAPK