The WD motif-containing protein receptor for activated protein kinase C (RACK1) is required for recruitment and activation of signal transducer and activator of transcription 1 through the type I interferon receptor

An obligatory step in the activation of Signal Transducers and Activators of Transcription (STATs) by cytokines is their docking to specific receptors via phosphotyrosines. However, this model does not address whether STATs pre-associate with their corresponding receptor or exist free in the cytoplasm before receptor activation. In this report, we demonstrate that pre-association of STAT1 with the receptor is required for type I interferon (IFN) signaling. Interestingly, the interaction between the human type I IFN receptor and STAT1 is not direct but mediated by the adapter protein receptor for activated protein kinase C (RACK1). Disruption of the IFN alpha receptor-RACK1 interaction abolishes not only IFN alpha -induced tyrosine phosphorylation of STAT1 but also activation of STATE, indicating that RACK1 plays a central role in early signaling through the Jak-STAT pathway. These findings demonstrate the involvement of RACK1 in STAT1 activation and raise the possibility that other STATs may pre-associate with cytokine receptors through similar adapter-STAT-mediated interactions.