Interferon a receptor 1 subunit (IFNaRI) binds to TYK2 and acts as a docking site for STAT2
Interferon a induces rapid tyrosine phosphorylation of its receptor, JAK1 and TYK2 tyrosine kinases, and STAT1 and STAT2 latent transcription factors. We have provided substantial direct evidence that STAT2 can bind to a phosphorylated tyrosine residue of IFNaRI in a SH2 dependent manner. Further, we have generated data suggesting that STATs dimerization drives the release of the phosphorylated STAT from the docking site. In addition, we independently confirmed the findings that the STAT2 and STAT1 are phosphorylated sequentially in the IFNa signaling pathway. We have also demonstrated the direct binding and phosphorylation of IFNaRI by TYK2 tyrosine kinase and provided the first detailed characterization of a JAK kinase binding site on a cytokine receptor and receptor binding site on the kinase. With this data, we are able to provide the first demonstration that point mutations which disrupt kinase-receptor binding also disrupt signaling. These observations are consistent with a model in which IFNaRI participates in initiating the IFNa signaling by mediating the interaction between JAK kinases and the STAT transcription factors.
Yan, H; Krishnan, K; Lim, JTE; Krolewski, J
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