TYK2 TYROSINE KINASE--NORMAL AND PATHOLOGIC FUNCTION

TYK2 酪氨酸激酶——正常和病理功能

• 批准号: 2774052
• 负责人: John J. Krolewski
• 金额: $ 15.03万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-04-10 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2774052
• 关键词: JAK kinase; active sites; binding proteins; biological signal transduction; cell growth regulation; cytokine receptors; genetic enhancer element; growth inhibitors; interferons; mutant; neoplastic cell; phosphorylation; protein structure function; receptor binding; tissue /cell culture; transcription factor; transfection

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.

描述：（改编自研究者的摘要）细胞内 信号通路将信息从细胞表面传递到 细胞核，控制细胞的生长、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 途径。对于受体型 PTK (rPTK)，配体结合 激活激酶，其自动磷酸化并随后结合 并磷酸化底物蛋白，启动信号级联反应。 一些非受体激酶与细胞形成“破碎的”受体复合物 表面分子和功能的方式完全类似于 rPTK。 tyk2PTK 是结构不同的亚家族的原型 非受体 PTK。它响应细胞因子而被激活 干扰素（IFN），它与一种或多种酪氨酸结合并磷酸化 IFN 受体的更多亚基。此外，它还是一种候选激酶 对于潜在转录因子家族的一个或多个成员， 称为 STAT（信号转导器和转录激活器）。 一旦这些蛋白质被酪氨酸磷酸化，它们就会转移到 细胞核，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。后一个属性可能 说明 IFN 在治疗多种疾病中的临床效用 惰性人类肿瘤。建议进行实验来表征， 详细来说，tyk2 激酶、IFN 之间的分子相互作用 受体亚基和 p113STST2 以研究 tyk2 的可能性 可能是一种肿瘤抑制剂。 具体来说，tyk2 蛋白的区域 (p135tyk2) 和干扰素受体参与相互关联 这两种蛋白质将被绘制。 接下来，磷酸化位点 tyk2 激酶和 IFN 受体都将被鉴定，并且作用 将确定信号传导途径中这些位点的数量。第三，一个 p135tyk2 的 STAT 蛋白磷酸化模型，其中 受体充当“对接”蛋白质，将进行测试。最后，他们将 检验 tyk2 的本构活性衍生物可以 在 IFN 敏感细胞系中充当肿瘤抑制剂。综上所述， 本提案中概述的研究计划应该会增加我们的理解 干扰素信号转导中发生的分子相互作用 途径，以及相关的细胞因子介导的途径并提供 深入了解控制人类肿瘤生长的机制， 也许有助于改进疗法的设计。