IKK:Biophysical basis of dynamic regulation

IKK：动态调节的生物物理基础

• 批准号: 8463406
• 负责人: GOURISANKAR GHOSH
• 金额: $ 50.65万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463406
• 关键词: Accounting; Adverse effects; Affect; Analytical Centrifugation; Architecture; Arthritis; Atherosclerosis; Binding; Binding Sites; Biochemical; Biochemical Reaction; Biochemistry; Biological Assay; Biophysics; Catalytic Domain; Cell Line; Cell Surface Receptors; Cells; Characteristics; Chronic; Chronic Disease; Complex; Computer Simulation; Coupled; Crystallography; Development; Disease; Dissociation; Dose; Drug Targeting; Effectiveness; Enzymes; Equation; Estimation Techniques; Family; Feedback; Genes; Genetic; Goals; Half-Life; Heat-Shock Proteins 90; Human Pathology; IkappaB kinase; Immune; Immune response; In Vitro; Inflammatory; Inflammatory Response; Interleukin-1; Intervention; Kinetics; Lesion; Libraries; Malignant Epithelial Cell; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Mediating; Methodology; Modeling; Molecular; Molecular Chaperones; Monitor; Multienzyme Complexes; NF-kappa B; Natural regeneration; Neoplasm Metastasis; Nucleotides; Outcome; Pathogenesis; Pathology; Pathway interactions; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacological Treatment; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Physiology; Play; Protein Dephosphorylation; Protein Kinase; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Reaction; Receptor Cell; Receptor Down-Regulation; Recycling; Regulation; Reporting; Rest; Role; Scaffolding Protein; Signal Transduction; Signaling Protein; Specificity; Squamous cell carcinoma; Stimulus; Stream; Structure; Structure-Activity Relationship; Study models; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tumor Necrosis Factor Receptor; Work; autocrine; base; cancer cell; cancer type; cell type; crosslink; cytokine; design; high throughput screening; immune activation; in vivo; inhibitor/antagonist; mathematical model; mutant; novel; paracrine; reaction rate; receptor; reconstitution; research study; response; self assembly; simulation; small molecule; src-Family Kinases; text searching; transcription factor; ubiquitin ligase; upstream kinase

IKK is the major signaling hub for inflammatory and innate immune responses. It is an enzyme complex that receives signals from a large number of cellular receptors regulates that activity of the NF-kB family of transcription factors. Misregulation of IKK is associated with many chronic diseases, such as chronic inflammatory pathologies (arthritis, atherosclerosis, etc) and many different types of cancer. Genetic evidence strongly supports IKK's critical and central role in many functions in physiology and pathology, but its potential as a drug target has not been realized. Mechanistic and biophysical studies have been lacking, and we have neither a kinetic understanding of IKK regulation nor structural information. However, what is clear is that IKK mediates signaling specificity by tight dynamic control that is stimulus-specific and induces the expression of specific sets of genes. Recent studies have reported on a tightly coupled activation and inactivation mechanism that can only be described by a multi-state activation-inactivation cycle that involves the function of several enzymes with different functions, such as ubiquitin ligases, kinases, phosphatases, and foldases. Through regulation of these activities, we hypothesize that the IKK cycle is driven in a stimulus- and cell type-specific manner, and that understanding the kinetic relationships will reveal opportunities for rationally targeted pharmacological intervention that discriminate between disease associated misregulation and stimulus-responsive regulation in healthy cells. In this proposal, we will construct a mathematical model of the IKK cycle to explore the dynamic regulation of IKK activity. We will then focus biochemical and biophysical studies on specific control mechanisms. In particular, we test the roles of IKK oligomerization, conformational changes, and upstream kinases in IKK activation and inhibition of IKK. Computational simulations will guide genetic and pharmacological manipulation of IKK dynamics. Finally, we will focus our study on how TNF and IL-1 produce differential dynamic control of IKK; how differential dose response and temporal control determine the efficacy of cytokine traps.

IKK 是炎症和先天免疫反应的主要信号中枢。它是一种酶复合物， 接收来自大量细胞受体的信号，调节 NF-kB 转录家族的活性 因素。 IKK 失调与许多慢性疾病有关，例如慢性炎症病理 （关节炎、动脉粥样硬化等）和许多不同类型的癌症。基因证据有力地支持了 IKK 的批评 在生理学和病理学的许多功能中发挥着核心作用，但其作为药物靶点的潜力尚未得到证实 意识到了。一直缺乏机理和生物物理研究，我们也没有对它的动力学了解。 IKK 监管或结构信息。然而，显而易见的是，IKK 通过紧密的介导信号特异性 动态控制是刺激特异性的并诱导特定基因组的表达。最近的研究有 报告了一种紧密耦合的激活和失活机制，只能用多状态来描述 激活-失活循环，涉及多种具有不同功能的酶的功能，例如泛素 连接酶、激酶、磷酸酶和折叠酶。通过对这些活动的监管，我们假设 IKK 循环以特定于刺激和细胞类型的方式驱动，并且理解动力学关系将有助于 揭示区分疾病的合理针对性药物干预的机会 健康细胞中相关的失调和刺激响应调节。 在本提案中，我们将构建IKK循环的数学模型来探索IKK的动态调控 活动。然后我们将重点研究特定控制机制的生化和生物物理研究。特别是，我们 测试 IKK 寡聚化、构象变化和上游激酶在 IKK 激活和抑制中的作用 IKK 的。计算模拟将指导 IKK 动力学的遗传和药理学操作。最后，我们 我们将重点研究 TNF 和 IL-1 如何对 IKK 产生差异动态控制；如何区分剂量反应 和时间控制决定了细胞因子陷阱的功效。

项目成果

Tunable signal processing through a kinase control cycle: the IKK signaling node.

通过激酶控制循环进行可调信号处理：IKK 信号节点。

• DOI: 10.1016/j.bpj.2013.05.013
• 发表时间: 2013-07-02
• 期刊: Biophysical journal
• 影响因子: 3.4
• 作者: M. Behar;A. Hoffmann
• 通讯作者: A. Hoffmann

Probing kinase activation and substrate specificity with an engineered monomeric IKK2.

使用工程单体 IKK2 探测激酶激活和底物特异性。

• 发表时间: 2014-04-01
• 影响因子: 2.9
• 作者: Hauenstein, Arthur V;Rogers, W Eric;Shaul, Jacob D;Huang, De;Ghosh, Gourisankar;Huxford, Tom
• 通讯作者: Huxford, Tom

Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-κB activation.

激酶信号复合体内的正反馈充当 NF-κB 激活的开关机制。

• 发表时间: 2014-05-16
• 作者: Shinohara, Hisaaki;Behar, Marcelo;Inoue, Kentaro;Hiroshima, Michio;Yasuda, Tomoharu;Nagashima, Takeshi;Kimura, Shuhei;Sanjo, Hideki;Maeda, Shiori;Yumoto, Noriko;Ki, Sewon;Akira, Shizuo;Sako, Yasushi;Hoffmann, Alexander;Kurosaki, Tomohiro;Ok
• 通讯作者: Ok