Integrin-filamin Interactions in Migration and Signaling

描述（由申请人提供）：要求支持分析肌动蛋白交联蛋白细丝蛋白和整联蛋白β亚基胞质尾之间的相互作用;这种相互作用对整联蛋白信号传导的影响;整联蛋白-细丝蛋白相互作用抑制细胞迁移的机制;以及如何在细胞中调节相互作用。异源二聚体整合素粘附受体介导整个发育过程中、止血期间以及对损伤和感染的反应中的细胞-细胞外基质和细胞-细胞粘附事件。特异性信号传导和细胞骨架蛋白与整合素β尾的结合控制细胞粘附、双向整合素信号传导并调节细胞运动性。整合素介导的细胞迁移对于发育、免疫应答以及组织重塑和伤口愈合至关重要。整合素介导的细胞迁移也有助于许多疾病状态，并且是肿瘤转移、炎症和动脉粥样硬化斑块形成所需的。细丝蛋白与整联蛋白β尾的增加的缔合抑制细胞迁移。申请人假设，细丝蛋白与整联蛋白β尾的调节性缔合介导不同的整联蛋白功能，并充当细胞迁移的制动器。为了验证这一假设，他的目标是绘制细丝蛋白中的整合素结合位点，并鉴定选择性抑制整合素结合的突变。他将使用这些突变体和以前鉴定的上调或下调细丝蛋白结合的整合素突变体来表征整合素-细丝蛋白相互作用对整合素介导的信号转导的影响。然后，他将研究细丝蛋白与整联蛋白结合增加后细胞迁移的抑制是否是由于观察到的对整联蛋白信号传导的影响，局部细丝蛋白介导的对肌动蛋白细丝交联的影响或两个过程的组合。最后，他将评估细丝蛋白水解、细丝蛋白或整联蛋白磷酸化以及整联蛋白和其他细丝蛋白结合蛋白之间的竞争对细丝蛋白与整联蛋白β尾的关联的影响。这些研究将表征控制细胞迁移的途径的调节和作用机制。细胞迁移是一个严格控制的过程，在许多生物现象中起着核心作用。因此，这些研究将提供对健康和疾病过程中必不可少的过程的深入了解，并可能确定治疗癌症，关节炎和动脉粥样硬化的新治疗靶点。

DESCRIPTION (provided by applicant): Support is requested to analyze the interaction between the actin crosslinking protein filamin and integrin beta subunit cytoplasmic tails; the effect this interaction has on integrin signaling; the mechanisms by which integrin-filamin interactions inhibit cell migration; and how the interaction is regulated in cells. Heterodimeric integrin adhesion receptors mediate cell-extracellular matrix and cell-cell adhesion events throughout development, during hemostasis and in the response to injury and infection. The binding of specific signaling and cytoskeletal proteins to integrin beta tails controls cell adhesion, bidirectional integrin signaling and regulates cell motility. Integrin-mediated cell migration is essential for development, the immune response, and for tissue remodeling and wound healing. Integrin-mediated cell migration also contributes to a number of disease states and is required for tumor metastasis, inflammation and the formation of atherosclerotic plaques. The increased association of filamin with integrin beta tails inhibits cell migration. The applicant hypothesizes that regulated association of filamin with integrin beta tails mediates distinct integrin functions and acts as a brake on cell migration. To test this hypothesis he aims to map the integrin binding site in filamin and identify mutations that selectively inhibit integrin binding. He will use these mutants and previously identified integrin mutants that up- or down-regulate filamin binding to characterize the effect of integrin-filamin interactions on integrin-mediated signal transduction. He will then investigate whether the inhibition of cell migration following increased filamin binding to integrins is due to the observed effects on integrin signaling, to local filamin-mediated effects on actin filament crosslinking or to a combination of both processes. Finally he will assess effect of filamin proteolysis, filamin or integrin phosphorylation and competition between integrins and other filamin-binding proteins on the association of filamin with integrin beta tails. These studies will characterize the regulation and mechanism of action of a pathway that controls cell migration. Cell migration is a tightly controlled process that plays a central role in many biological phenomena. Therefore these studies will provide insight into a process essential during health and disease and may identify novel therapeutic targets for treatment of cancers, arthritis and atherosclerosis.