CYTOKINE SIGNALING

干扰素和细胞因子在免疫应答中起关键作用。 在过去的几年中，已经清楚的是，细胞因子和干扰素利用类似的细胞内信号传导机制。 这些分子与其特异性受体的结合导致Jak家族的酪氨酸激酶的活化，所述酪氨酸激酶继而负责特异性酪氨酸上的受体亚基的磷酸化。 这些磷酸化的酪氨酸作为Stat因子的对接位点，将它们募集到受体复合物中，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，Stats是否保持在受体附近或游离在细胞质中。 在上一个资助期，我们提出，一些Stat因子可能直接或通过衔接蛋白与受体亚基组成相关。 我们证明，Stat 2是直接与β亚基的I型干扰素受体，甚至在受体磷酸化。 然而，我们没有证据表明其他Stats与细胞因子受体直接相关。我们现在已经克隆了一个衔接蛋白，它与负责间接与Stat 1相关的I型干扰素受体β链的同一区域相互作用。 在本申请中，我们将测试这种衔接蛋白作为受体β链和Stat 1之间的连接的假设。 我们还建议，这个适配器负责招募Stat 1到其他细胞因子受体，和/或可以作为其他Stats的适配器。最后，我们将确定这种衔接蛋白是否招募其他信号成分的受体复合物或负责不同的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.