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 o f Transcription (STATs) by cytokines is their docking to specific receptors via phosphotyrosines. However, this model does not address whether STATs p re-associate with their corresponding receptor or exist free in the cytopla sm before receptor activation. In this report, we demonstrate that pre-asso ciation of STAT1 with the receptor is required for type I interferon (IFN) signaling. Interestingly, the interaction between the human type I IFN rece ptor and STAT1 is not direct but mediated by the adapter protein receptor f or activated protein kinase C (RACK1). Disruption of the IFN alpha receptor -RACK1 interaction abolishes not only IFN alpha -induced tyrosine phosphory lation of STAT1 but also activation of STATE, indicating that RACK1 plays a central role in early signaling through the Jak-STAT pathway. These findin gs demonstrate the involvement of RACK1 in STAT1 activation and raise the p ossibility that other STATs may pre-associate with cytokine receptors throu gh similar adapter-STAT-mediated interactions.