The filopodial tip complex in adhesion, migration, and signaling

丝状伪足尖端复合体在粘附、迁移和信号传导中的作用

• 批准号: 10216311
• 负责人: RICHARD E CHENEY
• 金额: $ 43.07万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216311
• 关键词: Actins; Adhesions; Apical; Binding; Biological; Biological Process; Brain; Cancer Biology; Cell Adhesion; Cell membrane; Cells; Cellular biology; Chemotaxis; Child; Complex; Defect; Development; Disease; Embryonic Development; Epithelial Cells; Eye; Fiber; Filopodia; Fingers; Focal Adhesions; Genetic Diseases; Growth; Health; Heterogeneity; Human; Integrin beta Chains; Integrins; Knock-out; Link; Malignant Neoplasms; Malignant neoplasm of lung; Mammalian Cell; Microphthalmos; Mitosis; Mitotic; Molecular; Mus; Mutation; Myosin ATPase; Neoplasm Metastasis; Nerve; Neural Tube Closure; Paper; Pathway interactions; Patients; Physiological; Pigmentation physiologic function; Process; Prognosis; Property; Proteins; Reporting; Research; Resolution; Role; Signal Transduction; Site; Structure; Surface; Tail; Work; adhesion receptor; anticancer research; blood vessel development; cancer cell; cell motility; cellular microvillus; eye blood vessel; eye formation; human disease; live cell imaging; malignant breast neoplasm; melanoma; migration; monolayer; paxillin; polymerization; recessive genetic trait; structural biology; vasodilator-stimulated phosphoprotein; virtual

Project Summary/Abstract Filopodia are finger-like extensions of the plasma membrane that allow cells to contact and interact with their surroundings in processes such as nerve growth, blood vessel formation, and the spread of cancer cells. A poorly understood structure at the tips of filopodia, the filopodial tip complex, constitutes a key site of filopodial actin polymerization, adhesion, and signaling. Our research with myosin-X (Myo10) shows that it is a major component of the filopodial tip complex and recently revealed that it has important roles in mammalian development in neural tube closure, eye formation, blood vessel development, and pigmentation. A patient with microphthalmia (unusually small eyes) was recently shown to lack Myo10, strongly suggesting that mutations in Myo10 can cause recessive genetic disease in humans. A growing number of papers also show that Myo10 is a key protein in the invasion, metastasis, and division of cancer cells and is frequently upregulated in major human cancers. These and other observations make Myo10 an attractive target for anticancer research and make it essential to determine the fundamental cell biological functions of Myo10 and filopodial tip complex. Although filopodial tips can form specialized sites of adhesion, they lack core components of focal adhesions. Virtually all filopodial tips contain Myo10, a protein that we have shown can link actin to β-integrins, key molecules in cell adhesion. Because the assembly and composition of the tip complex and how it changes as it converts from extension to retraction or adhesion is not understood, we will: 1) Determine the composition of the filopodial tip complex during initiation, extension, retraction, and adhesion This aim will define the assembly pathway and states of the filopodia tip complex with respect to core filopodial tip components including Myo10, its putative interactor VASP, and capping protein. 2) Define the composition of the adhesions at the tips of mitotic retraction fibers. Although retraction fibers have the biologically crucial role of anchoring cells during mitosis, almost nothing is known about the composition of the adhesions at their tips. Myo10 is one of the few proteins known to localize to the tips of retraction fibers, so we will use it to investigate this poorly understood, but key site of cell adhesion. 3) Investigate the composition and functions of basolateral filopodia. We have discovered that in polarized epithelial cells Myo10 is targeted to the tips of filopodia on the basolateral surface rather than the apical microvilli on the same cells. Because Myo10 provides a probe for the tips of this largely uncharacterized class of filopodia, we will use it to investigate the basic cell biology of these structures. Together this research will define the basic properties of three poorly understood structure marked by Myo10 and the tip complex: filopodial tip adhesions, retraction fiber adhesions, and the filopodia on the basolateral surfaces of polarized epithelial cells.

项目摘要/摘要 丝状虫是质膜的手指样延伸，允许细胞接触并与其相互作用 神经生长，血管形成和癌细胞扩散等过程中的周围环境。 丝状尖端复合体的丝状尖端上的结构不足，构成了一个关键部位 丝状肌动蛋白聚合，粘合剂和信号传导。我们对Myosin-X（Myo10）的研究表明，这是一个 丝状尖端复合物的主要组成部分，最近透露它在哺乳动物中具有重要作用 神经元管闭合，眼睛形成，血管发育和色素沉着的发育。患者 最近证明了微观恐惧症（异常小的眼睛）缺乏肌无力，强烈暗示突变 在Myo10中，可能引起人类隐性遗传疾病。越来越多的论文也表明Myo10 是癌细胞侵袭，转移和分裂的关键蛋白质，经常在主要中进行更新 人类癌。这些和其他观察结果使Myo10成为抗癌研究和 确定Myo10和丝状尖端复合物的基本细胞生物学功能至关重要。 尽管丝状尖端可以形成粘合剂的专业位点，但它们缺乏焦点粘合剂的核心成分。 几乎所有的丝虫尖端都包含MyO10，我们已经显示的蛋白质可以将肌动蛋白与β-整合蛋白联系起来，钥匙 细胞粘附中的分子。因为尖端复合物的组装和组成以及它的变化 从扩展到缩回或粘合剂的转换，我们将： 1）确定在启动，扩展，撤回和 粘附这个目标将定义组装途径和丝状尖端配合物的状态 核心丝状尖端成分，包括Myo10，其推定的相互作用vasp和封盖蛋白。 2）在有丝分裂回收纤维的尖端上定义粘合剂的组成。虽然缩回 纤维在有丝分裂过程中具有生物学上至关重要的作用，几乎一无所知 粘附的尖端组成。 Myo10是已知的少数蛋白质之一 缩回纤维，因此我们将使用它来研究这种不良理解但细胞粘附的关键部位。 3）研究基底外侧丝霉菌的组成和功能。我们已经发现 偏振上皮细胞myo10针对基础表面上的丝状尖端，而不是 在同一细胞上的顶端微绒毛。因为Myo10提供了探测此大量未表征的技巧 丝状类别，我们将使用它来研究这些结构的基本细胞生物学。这项研究在一起 将定义三个以myo10和尖端复合体标记的三个不良理解结构的基本特性： 丝状尖端粘附，缩回纤维粘附和偏光表面上的丝状粘合剂 上皮细胞。