ACTIVATION OF PROTEIN-KINASE-A INHIBITS INTERFERON INDUCTION OF THE JAK STAT PATHWAY IN U266 CELLS/

Activation of early response genes by interferons (IFNs) requires tyro sine phosphorylation of the Stat transcription factors and is mediated by the Jak family of tyrosine kinases, Recent evidence suggests that ERK2 serine/threonine kinase modulates the IFN-stimulated Jak/Stat pat hway. In this report we show that in the myeloma cell line U266 protei n kinase A specifically interacts with the cytoplasmic domain of the I FN alpha/beta receptor, Treatment of cells with the adenylate cyclase activator forskolin inhibits IFN beta-, IFN gamma-, and hydrogen perox ide/vanadate-induced formation of complexes that bind to enhancers kno wn to stimulate the expression of IFN-regulated genes. Immunoprecipita tions followed by anti-phosphotyrosine immunoblots indicate that tyros ine phosphorylation of the alpha chain of the IFN alpha/beta receptor, Jak1, Trk2, as well as Stat1 and Stat2 is reduced as a consequence of incubation of cells with forskolin. In contrast, dideoxyforskolin, wh ich fails to activate adenylate cyclase, has no effect on IFN inductio n of the Jak/Stat pathway. These results indicate a novel regulatory m echanism by which protein kinase A can modulate the Jak/Stat signaling cascade.