TYK2 TYROSINE KINASE--NORMAL AND PATHOLOGIC FUNCTION

描述：(改编自研究人员的摘要)细胞内 信号通路将信息从细胞表面传递到 细胞核，控制两者的生长、分裂和分化 正常细胞和肿瘤细胞。蛋白酪氨酸激酶(PTK)是 负责触发其中许多事件的级联事件 小路。在受体类型PTKs(RPTKs)的情况下，配体结合 激活该激酶，使其自动磷酸化并随后结合 并使底物蛋白质磷酸化，启动信号级联反应。 一些非受体蛋白与细胞形成“破碎的”受体复合体。 表面分子和功能完全类似于 RPTKs。Tyk2PTK是一个结构不同的亚家族的原型 非受体蛋白酪氨酸激酶。它是在细胞因子的作用下被激活的 干扰素-(干扰素)，它结合和酪氨酸磷酸化一或 干扰素受体的亚基更多。此外，它还是一种候选的激酶 对于潜伏转录因子家族的一个或多个成员， 称为STATS(信号转导和转录激活子)。 一旦这些蛋白质被酪氨酸磷酸化，它们就会转移到 核，结合增强子元件并刺激干扰素特异性基因 抄写。由此产生的基因产物被认为促进了 抗病毒状态和/或抑制细胞生长。后一种属性可以 说明干扰素在多种疾病治疗中的临床应用 迟钝的人类肿瘤。实验的提出是为了刻画， 详细地说，TYK2激酶、干扰素之间的分子相互作用 受体亚基和p113STST2的表达，探讨TYK2 可能是一种肿瘤抑制因子。具体来说，TYK2蛋白的区域 (P135 Tyk2)与干扰素受体相互关联 这两种蛋白质将被绘制成图谱。接下来，蛋白上的磷酸化位点 TYK2激酶和干扰素受体都将被鉴定，其作用是 将确定信号通路中的这些位点中的哪些。第三，a P135tyk2诱导STAT蛋白磷酸化的模型 受体作为一种“对接”蛋白质，将被测试。最后，他们将 检验TYK2的结构性活性衍生物可以 在干扰素敏感细胞系中扮演肿瘤抑制因子的角色。总而言之， 这份提案中概述的研究计划应该会增加我们的理解 干扰素信号转导中的分子相互作用 途径，以及相关的细胞因子介导的途径和提供 洞察人类肿瘤生长的机制， 或许有助于改进疗法的设计。

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.