IFNAR1 signaling through STAT3, PI-3 kinase and NFkB

了解干扰素-α（IFN_）作用的分子基础是一个重要的目标， 干扰素在癌症、病毒性肝炎和多发性硬化症中的治疗潜力，以及其作为 了解细胞因子信号转导。IFNot通过调控基因表达发挥其生物学作用 通过酪氨酸磷酸化和STAT成员的激活（信号转导和 转录激活因子）蛋白家族。申请人发现，STAT3，一种急性胰腺炎的转录因子， 时相反应基因是IFN信号转导和诱导IFN生物学作用的关键元件。在 此外，还发现IFN通过激活NF-κ B（核因子-v_B）促进细胞存活， 涉及PI-3K（磷脂酰肌醇-3 '激酶）和Akt的丝氨酸激酶依赖性途径，以及 STAT3。基于这些发现，有待检验的一般假设是IFN_x受体整合了 涉及STAT3、PI-3K和NF-vJ3的信号通路。在具体目标1中，STAT3作为一种 将定义PI-3K的转录因子和衔接蛋白。拟议的研究将确定 STAT3中哪些特定氨基酸残基经历IFN依赖性磷酸化， 这些磷酸化事件对IFN的生物学作用，以及哪些IFN应答基因是STAT3- 监管.在具体目标2中，将定义NF-vJ3在IFNa作用中的作用。拟议的研究将 确定PI-3K/Akt介导的磷酸化事件与 IFN-γ、TRAFs（TNF受体相关因子）和NIK（NF-vJ3诱导激酶）在IFN-γ中的作用 诱导的NF-rJ3激活，NF-vJ3在IFN诱导基因中的作用，以及Iv33激酶的作用 复合物促进NF-κ B活化和细胞存活。尽管在IFN_x信号转导方面取得了进展， 通路，IFN_x的不同生物学作用的诱导机制仍然存在 不太了解。该提案的重点是表征信号通路的分子基础，因为它们 与IFN对细胞增殖和存活的作用有关。

Understanding the molecular basis of interferon-alpha (IFN_) action is an important goal when one considers IFN's therapeutic potential in cancer, viral hepatitis, and multiple sclerosis, as well as its role as a model for understanding cytokine signal transduction. IFNot elicits its biological actions by regulating gene expression through the tyrosine phosphorylation and activation of members of the STAT (signal transducers and activators of transcription) protein family. The applicant found that STAT3, a transcription factor for acute phase response genes, is a critical element in IFN signaling and induction of IFN's biological actions. In addition, it was also found that IFN promotes cell survival by activating NF-KB (nuclear factor-v_B) through a serine kinase-dependent pathway involving PI-3K (phosphatidylinositol-3' kinase) and Akt, as well as STAT3. Based on these findings, the general hypothesis to be tested is that the IFN_x receptor integrates signaling pathways involving STAT3, PI-3K and NF-vJ3. In Specific Aim 1, the role of STAT3 as a transcription factor and an adapter protein for PI-3K will be defined. The proposed studies will determine which specific amino acid residues in STAT3 undergo IFN-dependent phosphorylation, the relationship of these phosphorylation events to the biologic actions of IFN, and which IFN-responsive genes are STAT3- regulated. In Specific Aim 2, the role of NF-vJ3 in IFNa action will be defined. The proposed studies will define the relationship between PI-3K/Akt-mediated phosphorylation events and the anti-apoptotic action of IFN, the roles of TRAFs (TNF receptor-associated factors) and NIK (NF-vJ3-inducing kinase) in IFN- induced NF-rJ3 activation, the role of NF-vJ3 in gene induction by IFN, and the role of the Iv33 kinase complex in IFN promoted NF-KB activation and cell survival. Despite advances made on the IFN_x signaling pathway, the mechanisms that underlie the induction of the different biological actions of IFN_x remain poorly understood. This proposal focuses on characterizing the molecular basis of signaling pathways as they relate to 1FN action on cell proliferation and survival.