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Dexamethasone Induces Rapid Serine-Phosphorylation and Membrane Translocation of Annexin 1 in a Human Folliculostellate Cell Line via a Novel Nongenomic Mechanism Involving the Glucocorticoid Receptor, Protein Kinase C, Phosphatidylinositol 3-Kinase, and Mitogen-Activated Protein Kinase

Department of Neuroendocrinology (E.S., A.M., J.C.B.), Division of Neuroscience and Psychological Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 ONN, United Kingdom; Human Anatomy and Genetics (J.F.M., H.C.C.), University of Oxford, Oxford OX1 3QX; and Department of Biochemical Pharmacology (R.J.F.), The William Harvey Research Institute, London EC1M 6BQ, United Kingdom

Address all correspondence and requests for reprints to: Professor Julia Buckingham and Dr. Egle Solito, Department of Neuroendocrinology, Division of Neuroscience and Psychological Medicine, Faculty of Medicine, Imperial College London, Commonwealth Building, Hammersmith Hospital Campus, Du Cane Road, London W12 ONN, United Kingdom. E-mail: j.buckingham{at}imperial.ac.uk; e.solito{at}imperial.ac.uk.

Our recent studies on rat pituitary tissue suggest that the annexin 1 (ANXA1)-dependent inhibitory actions of glucocorticoids on ACTH secretion are effected via a paracrine mechanism that involves protein kinase C (PKC)-dependent translocation of a serine-phosphorylated species of ANXA1 (Ser-P-ANXA1) to the plasma membrane of the nonsecretory folliculostellate cells. In the present study, we have used a human folliculostellate cell line (PDFS) to explore the signaling mechanisms that cause the translocation of Ser-P-ANXA1 to the membrane together with Western blot analysis and flow cytometry to detect the phosphorylated protein. Exposure of PDFS cells to dexamethasone caused time-dependent increases in the expression of ANXA1 mRNA and protein, which were first detected within 2 h of steroid contact. This genomic response was preceded by the appearance within 30 min of substantially increased amounts of Ser-P-ANXA1 and by translocation of the phosphorylated protein to the cell surface. The prompt membrane translocation of Ser-P-ANXA1 provoked by dexamethasone was inhibited by the glucocorticoid receptor, antagonist, mifepristone, but not by actinomycin D or cycloheximide, which effectively inhibit mRNA and protein synthesis respectively in our preparation. It was also inhibited by a nonselective PKC inhibitor (PKC_9–31), by a selective inhibitor of Ca²⁺-dependent PKCs (Go 6976) and by annexin 5 (which sequesters PKC in other systems). In addition, blockade of phosphatidylinositiol 3-kinase (wortmannin) or MAPK pathways with PD 98059 or UO 126 (selective for MAPK kinse 1 and 2) prevented the steroid-induced translocation of Ser-P-ANXA1 to the cell surface. These results suggest that glucocorticoids induce rapid serine phosphorylation and membrane translocation of ANXA1 via a novel nongenomic, glucocorticoid receptor-dependent mechanism that requires MAPK, phosphatidylinositiol 3-kinase, and Ca²⁺-dependent PKC pathways.

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