Myosin-X and the molecular basis of filopodia function

肌球蛋白-X 和丝状伪足功能的分子基础

• 批准号: 7319196
• 负责人: RICHARD E CHENEY
• 金额: $ 29.88万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319196
• 关键词: Actins; Animals; Biochemical; Biological Process; Biology; Biophysics; Blood Vessels; Calcium; Calmodulin; Cell physiology; Cells; Cellular biology; Class; Complex; Exhibits; Family; Filopodia; Green Fluorescent Proteins; Growth; Health; Hearing; Hearing Impaired Persons; Human; Inherited; Intracellular Transport; Knock-out; Knockout Mice; Lead; Length; Life; Light; Localized; Microfilaments; Modeling; Molecular; Motor; Movement; Mutation; Myosin ATPase; Neoplasm Metastasis; Nerve; Nerve Regeneration; Numbers; Phenotype; Physiological; Process; Property; Range; Rate; Regulation; Research; Research Personnel; Resolution; Role; Shapes; Signal Transduction; Signaling Molecule; Stereocilium; Structure; System; Testing; Tissues; Total Internal Reflection Fluorescent; Usher Syndrome; Virus; Work; angiogenesis; base; cancer cell; cell motility; cellular engineering; cellular microvillus; deafness; fluorescence imaging; gastrointestinal microvillus; human disease; member; novel; programs; protein function; sensor; tool

DESCRIPTION (provided by applicant): Filopodia are slender cellular extensions that appear to function as cellular sensors that allow cells to interact with their surroundings in processes such as nerve growth, blood vessel formation, and the metastasis of cancer cells. Despite the central importance of filopodia and related structures such as microvilli and stereocilia, the molecular mechanisms that regulate the formation and function of these structures remain unclear. Growing evidence indicates that the MyTH4-FERM myosins, a newly recognized family of unconventional myosins, have critical roles as motor proteins that function in filopodia and related structures. Humans express four MyTH4-FERM myosins and mutations in two of these lead to hereditary deafness. We have discovered that myosin-X, a vertebrate-specific member of the MyTH4-FERM myosins that localizes to the tips of filopodia, is a remarkably potent inducer of filopodia, and undergoes a novel form of motility within filopodia. This has led us to hypothesize that myosin-X functions as a motor for a previously unsuspected system of intracellular transport within filopodia and related structures. We thus propose to: 1) Determine the molecular mechanisms by which myosin-X induces filopodia. 2) Investigate the basic properties of the novel system of intrafilopodial motility we have discovered. 3) Isolate full-length myosin-X and determine its fundamental biochemical properties 4) Determine the cellular and organismal functions of myosin-X using a mouse knock-out. By investigating myosin-X, the MyTH4-FERM myosin that is expressed in most vertebrate cells and tissues, this research will provide a model to investigate the fundamental cell biology of the MyTH4-FERM myosins and their roles in filopodia-like structures. This research is particularly relevant to deafness, since hearing depends on stereocilia, filopodia-like mechanosensors that contain a core of actin filaments. In addition, mutations in at least five other unconventional myosins are already known to cause human deafness, including Usher syndrome 1b, the leading cause of hereditary deaf-blindness. There is also growing evidence that filopodia can act as cellular highways that transport materials such as key signaling molecules and viruses, so studies of myosin-X function in filopodia will contribute to our understanding of the fundamental cell biology underlying nerve regeneration, angiogenesis, and the spread of cancer cells.

描述（由申请人提供）：丝状细胞延伸效应似乎是细胞传感器，使细胞在神经生长，血管形成和癌细胞的转移等过程中与周围环境相互作用。尽管丝状结构和相关结构（例如微绒毛和立体尾膜）的重要性，但调节这些结构的形成和功能的分子机制仍不清楚。越来越多的证据表明，神话4-肌蛋白是一个新认识的非常规肌蛋白家族，它作为运动蛋白的至关重要，在丝状蛋白质和相关结构中起作用。人类在其中两个中表达​​了四个神话肌蛋白和突变导致遗传性耳聋。我们已经发现，肌球蛋白-X是MyTh4-Ferm肌球蛋白的特定脊椎动物特异性成员，该肌球蛋白本地定位在丝状尖端，是一种非常有效的丝状诱导剂，并且在丝状卵形中具有新颖的运动形式。这使我们假设肌球蛋白X充当丝状及相关结构内细胞内转运系统的电动机。因此，我们建议：1）确定肌球蛋白-X诱导丝状菌素的分子机制。 2）研究我们发现的新型型内源运动系统的基本特性。 3）分离全长肌球蛋白-X并确定其基本生化特性4）使用小鼠敲除确定肌球蛋白-X的细胞和生物体功能。通过研究在大多数脊椎动物细胞和组织中表达的肌球蛋白X，这项研究将提供一个模型，以研究MyTH4-Ferm肌球蛋白的基本细胞生物学及其在类似丝状丝状结构中的作用。这项研究与耳聋特别相关，因为听力取决于立体胶质，含有丝状蛋白丝的核心的丝状机械传感器。此外，已经知道至少五种其他非常规肌蛋白的突变会引起人类耳聋，包括乌瑟综合征1B，这是遗传性聋哑人的主要原因。还有越来越多的证据表明，丝状疾病可以充当细胞高速公路，即传输诸如关键信号分子和病毒之类的材料，因此对丝状肌动蛋白肌动蛋白X功能的研究将有助于我们理解神经再生，血管生成和癌细胞扩散的基本细胞生物学。