TYK2 TYROSINE KINASE--NORMAL AND PATHOLOGIC FUNCTION

描述：（改编自研究者摘要）细胞内 信号传导通路将信息从细胞表面传递到细胞外表面， 细胞核，控制细胞的生长、分裂和分化 正常和肿瘤细胞。蛋白酪氨酸激酶（PTK）是 引发了一系列事件， 途径。在受体型PTK（rPTK）的情况下，配体结合 激活激酶，使其自身磷酸化， 并磷酸化底物蛋白，启动信号级联。 一些非受体激酶与细胞形成“断裂”的受体复合物 表面分子和功能的方式完全类似于 rPTKs。tyk 2 PTK是结构上不同的亚家族的原型 非受体PTKs。它被激活以响应细胞因子 干扰素-（IFN），并且其结合至一个或多个细胞并使其酪氨酸磷酸化， 更多的IFN受体亚基。此外，它还是一种候选激酶， 对于潜伏转录因子家族的一个或多个成员， 称为STAT（信号转导和转录激活因子）。 一旦这些蛋白质被酪氨酸磷酸化，它们就移位到 结合增强子元件并刺激IFN特异性基因 转录。由此产生的基因产物被认为可以促进 抗病毒状态和/或抑制细胞生长。后一种性质可以 解释了IFN在治疗各种 惰性的人类肿瘤。提出实验来表征， 详细地说，tyk 2激酶、IFN-γ和IFN-γ之间的分子相互作用， 受体亚基和p113 STST 2研究tyk 2 可能是肿瘤抑制因子。 具体来说，tyk 2蛋白的区域 （p135 tyk 2）和干扰素受体参与的相互关联， 这两种蛋白质将被定位。 接下来， tyk 2激酶和IFN受体都将被鉴定， 将确定这些位点在信号通路中的位置。三是 STAT蛋白被p135 tyk 2磷酸化的模型，其中 受体作为“对接”蛋白，将进行测试。最后，他们将 测试Tyk 2的组成型活性衍生物可以 在IFN敏感细胞系中作为肿瘤抑制因子。总而言之， 这项建议中概述的研究计划应该增加我们对 干扰素信号转导中的分子相互作用 途径，以及相关的精氨酸介导的途径，并提供 深入了解人类肿瘤生长的机制， 也许有助于设计更好的治疗方法。

DESCRIPTION: (adapted from the investigator's abstract) Intracellular signaling pathways transduce information from the cell surface to the nucleus, controlling the growth, division and differentiation of both normal and neoplastic cells. Protein tyrosine kinases (PTKs) are responsible for triggering the cascade of events in many of these pathways. In the case of receptor-type PTKs (rPTKs), ligand binding activates the kinase, which autophosphorylates and subsequently binds and phosphorylates substrate proteins, initiating the signaling cascade. Some non-receptor kinases form a "broken" receptor complex with a cell surface molecule and function in a manner completely analogous to the rPTKs. The tyk2PTK is the prototype of a structurally distinct subfamily of non-receptor PTKs. It is activated in response to the cytokine interferon- (IFN), and it binds to and tyrosine phosphorylates one or more subunits of the IFN receptor. In addition, it is a candidate kinase for one or more members of a family of latent transcription factors, known as STATs (signal transducers and activators of transcription). Once these proteins are tyrosine phosphorylated, they translocate to the nucleus, bind an enhancer element and stimulate IFN-specific gene transcription. The resulting gene products are believed to promote an anti-viral state and/or inhibit cell growth. This latter property may account for the clinical utility of IFN in the treatment of a variety of indolent human neoplasms. Experiments are proposed to characterize, in detail, the molecular interactions between the tyk2 kinase, the IFN receptor -subunit and p113STST2 to investigate the possibility that tyk2 may be a tumor suppressor. Specifically, the regions of the tyk2 protein (p135tyk2) and the IFN receptor involved in the mutual association of these two proteins will be mapped. Next, the phosphorylation sites on both the tyk2 kinase and IFN receptor will be identified, and the role of these sites in the signaling pathway will be determined. Third, a model for STAT protein phosphorylation by p135tyk2, in which the receptor acts as a "docking" protein, will be tested. Lastly, they will test the hypothesis that constitutively active derivatives of tyk2 can act as a tumor suppressor in an IFN-sensitive cell line. In summary, the research plan outlined in this proposal should increase our understanding of the molecular interactions occurring in the IFN signal transduction pathway, as well as related cytokine-mediated pathways and provide insight into the mechanisms governing the growth of human tumors, perhaps facilitating the design of improved therapies.