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AKAP95-mediated nuclear anchoring of PKA mediates cortisol-induced PTGS2 expression in human amnion fibroblasts

Nuclear signaling by the kinase PKA mediates activation of the transcription factor CREB in response to cortisol. PKA labors in the nucleus Stress hormone signaling is associated with the induction of labor in pregnancy. The stress hormone cortisol stimulates the production of the enzyme COX-2 in fetal membrane cells through induction of the transcription factor CREB. COX-2 produces prostaglandins, which generate positive feedback on the cells to produce more. Lu et al. found that the selective localization of the kinase PKA in the nucleus is critical to this mechanism in the fetal membranes. In human amnion fibroblasts taken from normal “term”-labor deliveries, compared to those from cesarean sections, the localization of PKA in the nucleus by interaction with AKAP95 enabled it to phosphorylate and activate CREB. These findings reveal additional molecular targets through which clinicians might induce labor or prevent it from initiating prematurely. The nuclear localization of PKA-AKAP95 introduces a new subcellular role for PKA signaling, potentially restricted to these highly specialized cells. Phosphorylation of the transcription factors cyclic adenosine monophosphate response element–binding protein (CREB) and signal transducer and activator of transcription 3 (STAT3) by protein kinase A (PKA) is required for the cortisol-induced production of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) in human amnion fibroblasts, which critically mediates human parturition (labor). We found that PKA was confined in the nucleus by A-kinase–anchoring protein 95 (AKAP95) in amnion fibroblasts and that this localization was key to the cortisol-induced expression of PTGS2, the gene encoding COX-2. Cortisol increased the abundance of nuclear PKA by stimulating the expression of the gene encoding AKAP95. Knockdown of AKAP95 not only reduced the amounts of nuclear PKA and phosphorylated CREB but also attenuated the induction of PTGS2 expression in primary human amnion fibroblasts treated with cortisol, whereas the phosphorylation of STAT3 in response to cortisol was not affected. The abundances of AKAP95, phosphorylated CREB, and COX-2 were markedly increased in human amnion tissue after labor compared to those in amnion tissues from cesarean sections without labor. These results highlight an essential role for PKA that is anchored in the nucleus by AKAP95 in the phosphorylation of CREB and the consequent induction of COX-2 expression by cortisol in amnion fibroblasts, which may be important in human parturition.