Guanine nucleotide exchange factor Epac2-dependent activation of the GTP-binding protein Rap2A mediates cAMP-dependent growth arrest in neuroendocrine cells [Neurobiology]

First messenger-dependent activation of MAPKs in neuronal and endocrine cells is critical for cell differentiation and function and requires guanine nucleotide exchange factor (GEF)- mediated activation of downstream Ras-family small GTPases, which ultimately lead to ERK, JNK, and p38 phosphorylation. Because there are numerous GEFs and also a host of Ras-family small GTPases, it is important to know which specific GEF-small GTPase dyad functions in a given cellular process. Here, we investigated the upstream activators and downstream effectors of signaling via the GEF Epac2 in the neuroendocrine NS-1 cell line. Three cAMP sensors, Epac2, PKA and NCS-Rapgef2 mediate distinct cellular outputs: p38-dependent growth arrest, CREB-dependent cell survival, and ERKdependent neuritogenesis, respectively, in these cells. Previously, we found that cAMP-induced growth arrest of PC12 and NS-1 cells requires Epac2-dependent activation of p38 MAPK, which posed the important question of how Epac2 engages p38 without simultaneously activating other MAPKs in neuronal and endocrine cells. We now show that the small GTP-binding protein Rap2A is the obligate effector for, and GEF substrate of, Epac2 in mediating growth arrest through p38 activation in NS-1 cells. This new pathway is distinctly parcellated from the GPCR → Gs → AC → cAMP → PKA → CREB pathway mediating cell survival, and the GPCR → Gs → AC → cAMP → NCS-Rapgef2 → B-Raf → MEK → ERK pathway mediating neuritogenesis in NS-1 cells.

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