Signal Transduction by alphaVbeta8 Integrin

alphaVbeta8 整合素的信号转导

• 批准号: 8816863
• 负责人: Joseph H McCarty
• 金额: $ 36.03万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816863
• 关键词: Adaptor Signaling Protein; Address; Adhesions; Affinity; Amino Acid Motifs; Amino Acid Sequence; Antibodies; Binding; Biochemistry; Biosensor; Blood Vessels; Brain; Breast; Cell Culture System; Cell-Cell Adhesion; Cells; Colon; Complex; Cues; Cytoplasmic Tail; Cytoskeleton; Development; Disease; Energy Transfer; Event; Extracellular Matrix; Extracellular Matrix Proteins; Fluorescence Microscopy; Focal Adhesions; GDP dissociation inhibitor 1; Gene Expression; Genetic; Genetic Screening; Genetically Engineered Mouse; Health; Human; Information Management; Integrins; Knowledge; Life; Ligands; Link; Mass Spectrum Analysis; Mediating; Modeling; Multiprotein Complexes; Mus; Neuraxis; Normal tissue morphology; Output; PTPN12 gene; Pathology; Pattern; Peptides; Phosphorylation; Physiology; Play; Primary Cell Cultures; Protein Tyrosine Phosphatase; Protein phosphatase; Proteins; Proteomics; Regulation; Reporting; Role; Scaffolding Protein; Serine; Serine/Threonine Phosphorylation; Signal Transduction; Signal Transduction Pathway; Skin Cancer; System; Talin; Tamoxifen; Tertiary Protein Structure; Threonine; Transforming Growth Factors; Tyrosine Phosphorylation; Variant; Work; base; cell growth; cell motility; cell type; extracellular; in vivo; integrin alphavbeta8; interdisciplinary approach; knockout gene; link protein; migration; mimetics; mouse model; novel; protein complex; protein protein interaction; receptor; research study; response; rho; rho GTP-Binding Proteins; spatiotemporal; spinophilin; tool

DESCRIPTION (provided by applicant): Cells are information management machines that must interpret a milieu of extracellular cues to control outputs ranging from proliferation to differentiation and migration. Integrins are ab heterodimeric proteins that link the extracellular matrix (ECM) to the cytoskeleton and control intracellular signaling cascades. While a great deal is known about adhesion and signaling functions for most integrins, signal transduction pathways regulated by integrin avb8, which was discovered more than 20 years ago, remain largely unexplored. avb8 integrin contains several novel features that suggest unique signaling functions. For example, the primary amino acid sequence of the b8 cytoplasmic tail is divergent from other integrins, suggesting interactions with atypical signaling effectors. In addition, b8 integrin lacks an extracellular "deadbolt" domain that in other integrins modulates inside-out activation, suggesting different mechanisms of ECM affinity regulation. The PI's group has performed genetic screens and proteomic-based experiments to identify intracellular signaling effectors that bind to b8 integrin, but not to other integrin subunits. In this project we will anayze how these effector proteins contribute to avb8 integrin-mediated cell migration using genetically engineered mouse models and primary culture systems. In Aim 1 we will characterize links between avb8 integrin, the cytoplasmic tyrosine phosphatase PTP-PEST, and the Rho GTPase effector protein RhoGDI1. In Aim 2 functional interactions between avb8 integrin and Spinophilin, a cytoskeletal scaffolding protein and regulatory subunit of the serine/threonine protein phosphatase 1 (PP1), will be analyzed. Lastly, integrin-dependent links between Spinophilin/PP1, PTP-PEST and Rho signaling will be explored. In summary, experiments in this project will reveal new and important mechanisms underlying avb8 integrin control of cell adhesion and migration in development and disease.

描述（由申请人提供）：细胞是信息管理机器，必须解释细胞外环境环境以控制从增殖到分化和迁移的输出。整合素是将细胞外基质 (ECM) 连接到细胞骨架并控制细胞内信号级联的 ab 异二聚体蛋白。虽然人们对大多数整合素的粘附和信号传导功能了解很多，但 20 多年前发现的整合素 avb8 调节的信号转导途径仍然很大程度上未被探索。 avb8 整合素包含几个新颖的特征，表明其具有独特的信号传导功能。例如，b8 胞质尾部的一级氨基酸序列与其他整联蛋白不同，表明与非典型信号传导效应子存在相互作用。此外，b8 整合素缺乏细胞外“死栓”结构域，而其他整合素则调节由内而外的激活，这表明 ECM 亲和力调节的不同机制。 PI 的团队进行了遗传筛选和基于蛋白质组学的实验，以确定与 b8 整合素结合但不与其他整合素亚基结合的细胞内信号传导效应器。在这个项目中，我们将使用基因工程小鼠模型和原代培养系统分析这些效应蛋白如何促进 avb8 整合素介导的细胞迁移。在目标 1 中，我们将描述 avb8 整合素、细胞质酪氨酸磷酸酶 PTP-PEST 和 Rho GTP 效应蛋白 RhoGDI1 之间的联系。在目标 2 中，将分析 avb8 整合素和 Spinophilin（一种细胞骨架支架蛋白和丝氨酸/苏氨酸蛋白磷酸酶 1 (PP1) 的调节亚基）之间的功能相互作用。最后，将探讨 Spinophilin/PP1、PTP-PEST 和 Rho 信号传导之间的整合素依赖性联系。总之，该项目的实验将揭示avb8整合素控制发育和疾病中细胞粘附和迁移的新的重要机制。