The Coordination of Cytoskeletal Dynamics by Coronins

Coronins 协调细胞骨架动力学

• 批准号: 7351070
• 负责人: JAMES E BEAR
• 金额: $ 26.74万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-28 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7351070
• 关键词: Actins; Amino Acids; Annona muricata coronin; Back; Biochemical; Biological; Biological Assay; Biological Markers; Cell membrane; Cells; Complex; Cytoskeleton; Data; Disseminated Malignant Neoplasm; Filament; Gene Expression; Generations; Human; Immune response; In Vitro; Localized; Membrane; Microfilaments; Monoclonal Antibodies; Morphogenesis; Neoplasm Metastasis; Pathologic Processes; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Physiological Processes; Play; Positioning Attribute; Protein Dephosphorylation; Proteins; Regulation; Role; Sampling; Serine; Testing; Time; Visual; WD Repeat; Work; Wound Healing; base; cell motility; cofilin; comparative; coronin protein; density; depolymerization; human EMS1 protein; in vivo; insight; melanoma; mimetics; mutant; neoplastic cell; research study; tumor

DESCRIPTION (provided by applicant): Cell migration is essential for many physiological processes such as wound healing, immune response and morphogenesis, and plays a significant role in pathological processes such as cancer metastasis. In order for cells to migrate, they must actively and coordinately remodel their actin cytoskeleton on a time scale of seconds. The control of actin dynamics requires dozens of proteins, but two critical components are the Arp2/3 complex that nucleates new filaments in branched arrays and ADF/Cofilin proteins that promote actin filament turnover by severing and enhanced depolymerization. It has long been suspected that these two factors function in a coordinated manner, but the mechanism of this coordination was unknown. Recent data from our lab indicate that Coronins, highly conserved WD-repeat proteins, have a unique function as coordinators of Arp2/3 and Cofilin activity at the leading edge of motile cells. This proposal seeks to elucidate the mechanisms of this coordination and determine how this activity contributes to cell migration and cancer metastasis. To achieve this, we propose four specific aims: 1) The regulation of Arp2/3 function by Coronin 1B; 2) The regulation of Cofilin activity by Coronin 1B via the Slingshot phosphatases; 3) The spatial and temporal control of Coronin 1B activity by Ser2 phosphorylation; and 4) The comparative analysis of Coronin 1B and Coronin 1C regulation and function.

描述（由申请人提供）：细胞迁移对于许多生理过程如伤口愈合、免疫应答和形态发生是必不可少的，并且在病理过程如癌症转移中起重要作用。为了使细胞迁移，它们必须在数秒的时间尺度上积极协调地重塑它们的肌动蛋白细胞骨架。肌动蛋白动力学的控制需要几十种蛋白质，但两个关键的组成部分是Arp 2/3复合物和ADF/Cofilin蛋白，Arp 2/3复合物使分支阵列中的新丝成核，ADF/Cofilin蛋白通过切断和增强解聚来促进肌动蛋白丝的周转。长期以来，人们一直怀疑这两个因素以协调的方式发挥作用，但这种协调的机制尚不清楚。我们实验室的最新数据表明，Coronins，高度保守的WD-重复蛋白，具有独特的功能，作为Arp 2/3和Cofilin活性的协调员在运动细胞的前沿。该提案旨在阐明这种协调的机制，并确定这种活动如何有助于细胞迁移和癌症转移。为了实现这一点，我们提出了四个具体的目标：1）Arp 2/3功能的调节冠状蛋白1B; 2）Cofilin活性的调节冠状蛋白1B通过弹弓磷酸酶; 3）的空间和时间的控制冠状蛋白1B活性的丝氨酸2磷酸化;和4）冠状蛋白1B和冠状蛋白1C的调节和功能的比较分析。