G-protein-coupled receptors mediate 14-3-3 signal transduction

G-protein-coupled receptor(GPCR)-interacting proteins likely participate in regulating GPCR signaling by eliciting specific signal transduction cascades,inducing cross-talk with other pathways,and fine tuning the signal.However,except for G-proteins andβ-arrestins,other GPCR-interacting proteins are poorly characterized.14-3-3 proteins are signal adaptors,and their participation in GPCR signaling is not well understood or recognized.Here we demonstrate that GPCR-mediated 14-3-3 signaling is ligandregulated and is likely to be a more general phenomenon than suggested by the previous reports of 14-3-3 involvement with a few GPCRs.For the first time,we can pharmacologically characterize GPCR/14-3-3 signaling.We have shown that GPCR-mediated 14-3-3 signaling is phosphorylation-dependent,and that the GPCR/14-3-3 interaction likely occurs later than receptor desensitization and internalization.GPCR-mediated 14-3-3 signaling can beβ-arrestin-independent,and individual agonists can have different potencies on 14-3-3 andβ-arrestin signaling.GPCRs can also mediate the interaction between 14-3-3 and Raf-1.Our work opens up a new broad realm of previously unappreciated GPCR signal transduction.Linking GPCRs to 14-3-3 signal transduction creates the potential for the development of new research directions and provides a new signaling pathway for drug discovery.