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Published on: March 2, 2018
Separate cyclic AMP sensors for neuritogenesis, growth arrest, and survival of neuroendocrine cells
Andrew C Emery1, Maribeth V Eiden, Lee E Eiden
1From the Section on Molecular Neuroscience and.
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.
Insights
Cyclic AMP (cAMP) and nerve growth factor (NGF) trigger neuroendocrine cell differentiation via distinct pathways. cAMP uses specific sensors for neurite extension and growth arrest, while NGF acts independently, highlighting insulated signaling mechanisms.
Area of Science:
- Cellular Biology
- Neuroscience
- Molecular Signaling
Background:
- Neuroendocrine cells differentiate into neuronal phenotypes stimulated by G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs).
- Elevated cyclic AMP (cAMP) levels are a key second messenger in GPCR-mediated differentiation.
- Nerve growth factor (NGF), acting via RTKs, also induces differentiation.
Purpose of the Study:
- To investigate the distinct signaling pathways mediating cAMP- and NGF-induced differentiation in neuroendocrine cells.
- To determine if specific cAMP sensors are required for different aspects of differentiation, such as neurite extension and growth arrest.
- To elucidate the relationship between cAMP- and NGF-dependent signaling cascades.
Main Methods:
- Utilized PC12 and NS-1 cell lines to study differentiation.
- Manipulated cAMP levels and NGF signaling to observe cellular responses.
- Investigated the roles of specific cAMP sensors, including neuritogenic cyclic AMP sensor/Rapgef2 and Epac2.
- Analyzed downstream signaling pathways involving ERK and p38 MAP kinases.
- Assessed cell survival under serum withdrawal conditions.
Main Results:
- cAMP-induced neurite extension is mediated by neuritogenic cyclic AMP sensor/Rapgef2 signaling to ERK.
- cAMP-induced growth arrest is mediated by Epac2 signaling to p38 MAP kinase.
- These cAMP-dependent processes do not require transactivation of TrkA (NGF receptor).
- NGF-induced differentiation relies on independent activation of ERK and p38, bypassing cAMP sensors (PKA, Epac, Rapgef2).
- Both cAMP and NGF protect against serum withdrawal-induced cell death via separate signaling pathways.
Conclusions:
- cAMP- and NGF-dependent differentiation pathways are distinct and insulated.
- Specific cAMP sensors differentially regulate neurite extension and growth arrest.
- NGF utilizes independent signaling cascades for differentiation and cell survival.
- Understanding these distinct pathways offers insights into neuroendocrine cell differentiation and survival mechanisms.
