Integrin-filamin Interactions in Migration and Signaling

描述(申请人提供)：需要支持分析肌动蛋白交联蛋白细丝和整合素β亚单位细胞质尾巴之间的相互作用；这种相互作用对整合素信号的影响；整合素-细丝相互作用抑制细胞迁移的机制；以及这种相互作用在细胞中是如何调节的。异二聚体整合素黏附受体介导细胞-细胞外基质和细胞-细胞黏附事件，在整个发育、止血和对损伤和感染的反应中。特定的信号和细胞骨架蛋白与整合素β尾巴结合，控制细胞黏附，双向整合素信号转导，调节细胞运动。整合素介导的细胞迁移对于发育、免疫反应、组织重塑和伤口愈合是必不可少的。整合素介导的细胞迁移也与多种疾病状态有关，是肿瘤转移、炎症和动脉粥样硬化斑块形成所必需的。丝氨酸与整合素β尾巴的结合增加抑制了细胞的迁移。申请人假设，丝素与整合素β尾巴的受控结合调节了不同的整合素功能，并对细胞迁移起到了刹车的作用。为了验证这一假设，他的目标是绘制丝氨酸中整合素结合位点的图谱，并识别选择性抑制整合素结合的突变。他将使用这些突变体和先前发现的上调或下调细丝素结合的整合素突变体来表征整合素-细丝素相互作用对整合素介导的信号转导的影响。然后，他将研究细丝素与整合素结合增加后对细胞迁移的抑制是由于观察到的对整合素信号的影响，还是由于局部细丝素对肌动蛋白细丝交联的影响，还是两种过程的结合。最后，他将评估细丝蛋白分解、细丝或整合素磷酸化以及整合素与其他细丝素结合蛋白之间的竞争对细丝素与整合素β尾巴结合的影响。这些研究将描述控制细胞迁移的途径的调节和作用机制。细胞迁移是一个受到严格控制的过程，在许多生物现象中发挥着核心作用。因此，这些研究将提供对健康和疾病中必不可少的过程的洞察，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.