NEGATIVE REGULATION OF INTERLEUKIN-4 SIGNALING

INTERLEUKIN-4 信号传导的负调控

基本信息

批准号：
6636379
负责人：
SAIKH JAHARUL HAQUE
金额：
$ 19.54万
依托单位：
CLEVELAND CLINIC FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-03-01 至 2004-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6636379
关键词：
binding proteins biological signal transduction cytokine receptors enzyme complex enzyme structure enzyme substrate interleukin 4 laboratory mouse protein tyrosine phosphatase

项目摘要

Cytokines control many important cellular responses by activating intracellular signaling cascades including the Jak-Stat pathway that leads to the transcriptional activation of specific genes. The regulation of cytokine signaling requires a delicate balance between biochemical events that activate and amplify the signals initiated by the cytokine receptor-associated Jaks, and the mechanisms that inactivate the Jaks and thereby attenuate the signals. Although biochemical mechanisms responsible for initiation and amplification of cytokine signals have precisely been defined in the recent years, negative regulation of cytokine signaling remains poorly understood. The long term goal of this application is to investigate cellular mechanisms responsible for the negative control of cytokine signaling, using the IL-4 signaling system as a paradigm. IL-4 plays multiple roles in host defense and immunity. It regulates growth and differentiation of B and T cells and is recognized as an important determinant of the nature of the immune response through the promotion of humoral response at the expense of cell mediated immunity. IL-4 activates two intracellular signaling cascades in target cells: the IRS-PI3-Kinase pathway that leads to cell proliferation, and the Jak-Stat pathway that induces the transcription of a number of specific genes. Both pathways are activated by Jak-mediated tyrosine phosphorylation of specific proteins. Our preliminary work has identified a protein tyrosine phosphatase Shp-1 and two suppressor of cytokine signaling (SOCS)-family proteins SOCS-1 and SOCS-3 as negative regulators of IL-4-dependent signal transduction. In this application we propose the hypotheses that (i) IL-4 receptor activation is negatively controlled by Shp-1 and additional protein tyrosine phosphatases(s) (PTPs) at an early phase, and (ii) IL-4-inducible proteins SOCS-1 and SOCS-3 down-regulate the receptor activation in late phase, by acting through a feedback loop. We will test these hypotheses by pursuing the following specific aims. (1) To define the roles of PTPs in the negative regulation of IL-4 signaling we will identify Shp-1 substrate(s), investigate the structural basis of the functional difference between Shp-1 and Shp-2, and identify additional PTPs that associate with the IL-4Ra complex and inhibits receptor activation. (2) To investigate the roles of specific SOCS-family proteins in the negative regulation of IL-4 signaling we will define the structural basis and molecular mechanisms of SOCS-1- and SOCS-3-mediated inhibition, and determine how the constitutive or induced expression of SOCS-1 and SOCS-3 prior to the initiation of IL-4 receptor activation affects the signaling process.

细胞因子通过激活细胞内信号级联控制许多重要的细胞反应，包括导致特定基因转录激活的 Jak-Stat 途径。细胞因子信号传导的调节需要在激活和放大细胞因子受体相关 Jaks 引发的信号的生化事件与灭活 Jaks 从而减弱信号的机制之间建立微妙的平衡。尽管近年来已经精确定义了负责启动和放大细胞因子信号的生化机制，但对细胞因子信号传导的负调控仍然知之甚少。该应用的长期目标是使用 IL-4 信号系统作为范例，研究负责细胞因子信号传导负控制的细胞机制。 IL-4 在宿主防御和免疫中发挥多种作用。它调节 B 细胞和 T 细胞的生长和分化，并通过以细胞介导的免疫为代价促进体液反应，被认为是免疫反应性质的重要决定因素。 IL-4 激活靶细胞中的两个细胞内信号级联：导致细胞增殖的 IRS-PI3-激酶途径，以及诱导许多特定基因转录的 Jak-Stat 途径。这两条途径均由 Jak 介导的特定蛋白质酪氨酸磷酸化激活。我们的初步工作已确定蛋白酪氨酸磷酸酶Shp-1和细胞因子信号传导抑制因子(SOCS)家族蛋白SOCS-1和SOCS-3作为IL-4依赖性信号转导的负调节因子。在本申请中，我们提出假设：(i) IL-4 受体激活在早期受到 Shp-1 和其他蛋白酪氨酸磷酸酶 (PTP) 的负控制，以及 (ii) IL-4 诱导蛋白 SOCS -1 和 SOCS-3 通过反馈回路发挥作用，下调晚期受体激活。我们将通过追求以下具体目标来检验这些假设。 (1) 为了定义 PTP 在 IL-4 信号传导负调节中的作用，我们将鉴定 Shp-1 底物，研究 Shp-1 和 Shp-2 之间功能差异的结构基础，并鉴定其他 PTP与 IL-4Ra 复合物结合并抑制受体激活。 (2) 为了研究特定 SOCS 家族蛋白在 IL-4 信号传导负调节中的作用，我们将定义 SOCS-1 和 SOCS-3 介导的抑制的结构基础和分子机制，并确定组成型或在 IL-4 受体激活开始之前诱导的 SOCS-1 和 SOCS-3 表达会影响信号传导过程。