CYTOKINE SIGNALING

干扰素和细胞因子在免疫反应中起着关键作用。在过去的几年里，细胞因子和干扰素利用相似的细胞内信号传递机制已经变得清晰起来。这些分子与其特定受体的结合导致JAK家族酪氨酸激酶的激活，进而负责特定酪氨酸受体亚单位的磷酸化。这些磷酸化的酪氨酸作为Stat因子的对接部位，将它们招募到受体复合体，在那里它们将被Jak激酶磷酸化。一个尚未解决的关键问题是，在静息状态下，Stat是保持在受体附近还是在细胞质中游离。在之前的资助时期，我们提出了一些STAT因子可能直接或通过接头蛋白与受体亚单位有结构性关联。我们证明，STAT2甚至在受体磷酸化之前就与I型干扰素受体的β亚基直接相关。然而，我们没有证据表明其他STAT与细胞因子受体直接相关。我们现在已经克隆了一种接头蛋白，它与I型干扰素受体β链的同一区域相互作用，负责间接与STAT1联系。在目前的应用中，我们将测试这个适配器蛋白作为受体的β链和STAT1之间的链接的假设。我们还认为，该接头负责将STAT1募集到其他细胞因子受体，和/或可能作为其他STAT的接头。最后，我们将确定该接头蛋白是否将其他信号成分招募到受体复合体中，或者负责不同信号通路之间的串扰。

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.