NEGATIVE REGULATION OF INTERLEUKIN-4 SIGNALING

INTERLEUKIN-4 信号传导的负调控

• 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
• 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

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传导级联反应来控制许多重要的细胞反应，其中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由细胞因子受体相关的JAK引发的信号的生化事件之间取得微妙的平衡，以及使JAKS失活的机制，从而减轻了信号。 尽管近年来已经确切地定义了负责启动和扩增细胞因子信号的生化机制，但细胞因子信号传导的负调控仍然很少了解。 该应用的长期目标是使用IL-4信号系统作为范式研究负责细胞因子信号的负面对照的细胞机制。 IL-4在宿主防御和免疫力中扮演多个角色。 它调节了B和T细胞的生长和分化，并被认为是通过促进体液反应以牺牲细胞介导的免疫力为代价来确定免疫反应性质的重要决定因素。 IL-4激活目标细胞中的两个细胞内信号传导级联反应：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。 两种途径均通过JAK介导的特定蛋白质酪氨酸磷酸化激活。我们的初步工作已经确定了蛋白质酪氨酸磷酸酶SHP-1和两个细胞因子信号传导（SOCS） - 家族蛋白SOCS-1和SOCS-3的抑制剂是IL-4依赖性信号传输的负调节剂。 在此应用中，我们提出了以下假设：（I）IL-4受体激活受SHP-1和其他蛋白质酪氨酸磷酸酶（S）（PTP）的负面控制，以及（ii）IL-4-诱导蛋白SOCS-SOCS-1和SOCS-3通过通过送送送回送送送送纸的后期，将受体激活下调。 我们将通过追求以下特定目标来检验这些假设。 （1）为了定义PTP在IL-4信号的负调控中的作用，我们将识别SHP-1底物，研究SHP-1和SHP-2之间功能差的结构基础，并确定与IL-4RA复合物相关的其他PTP，并识别受体激活。 (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.