Interferons and cytokines play a critical role in immune responses. Over the last years, it has become clear that cytokines and interferons utilize similar mechanisms of intracellular signaling. Binding of these molecules to their specific receptors results in activation of tyrosine kinases of the Jak family, that are in turn responsible for phosphorylation of receptor subunits on specific tyrosines. These phosphorylated tyrosines serve as docking sites for Stat factors, recruiting them to the receptor complex where they will be phosphorylated by Jak kinases. A critical question that has not been addressed is whether in the resting state Stats are maintained in the proximity of the receptors or are free in the cytoplasm. In the previous funding period we proposed that some Stat factors may be constitutively associated to receptor subunits either directly or through adaptor proteins. We demonstrated that Stat2 is directly associated with the beta subunit of the type I interferon receptor even before receptor phosphorylation. However, we have no evidence of the direct association of other Stats with cytokine receptors. We have now cloned an adaptor protein that interacts with the same region of the beta chain of the type I interferon receptor that is responsible for associating indirectly with Stat1. In the current application we will test the hypothesis that this adaptor protein serves as link between the beta chain of the receptor and Stat1. We also propose that this adaptor is responsible for the recruitment of Stat1 to other cytokine receptors, and/or may serve as an adaptor for other Stats. Finally, we will determine whether this adaptor protein recruits other signaling components to the receptor complex or is responsible for the cross-talk between different signaling pathways.
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