Filopodia assembly by FMNL3: biochemical mechanism and cellular function

FMNL3 的丝状伪足组装:生化机制和细胞功能

基本信息

  • 批准号:
    8669584
  • 负责人:
  • 金额:
    $ 31.19万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-01-01 至 2018-11-30
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract Filopodia are actin-based finger-like protrusions from the plasma membrane, and are used for multiple functions in cells including motility, cell-cell adhesion, cell-substratum adhesion, and viral infection. For many of these processes, the filopodia involved are highly dynamic, assembling and disassembling on a time scale of minutes. At least three actin-based activities are required for filopodial assembly: filament nucleation activity, filament elongation activity, and filament bundling activity. Two competing models for filopodial assembly differ in the nature of the nucleation and elongation activities. In the "tip nucleation" model, proteins such as formins act as both nucleation and elongation factors. In the "convergent elongation" model, Arp2/3 complex is the nucleation factor, with formins subsequently acting as elongation factors that also help re-model the branched Arp2/3-generated actin network. Our results show that the formin FMNL3 is a potent filopodial assembly factor, and we propose a novel extension to the convergent elongation model - that FMNL3 can remodel any existing filaments (Arp2/3-dependent or Arp2/3-independent) to filopodia, provided they abut the plasma membrane. In addition, we show that FMNL3 acts in cell-cell adhesion. In this proposal, we study FMNL3 in mammalian cells, focusing on the following aims. Aim 1 uses cell-based assays to define the mechanism of FMNL3-mediated filopodial assembly. We use live-cell microscopy, inhibitor treatments and siRNA to test the ability of FMNL3 to re-model stress fiber/focal adhesion-associated actin filaments into filopodia. Aim 2 uses a cell-free system to reconstitute filopodial assembly on supported lipid bilayers using purified proteins (FMNL3, Arp2/3 complex, capping protein, profilin, fascin). With this system, we will test assembly principles in a controlled manner and investigate the contributions of other molecules (VASP, cofilin). Aim 3 investigates FMNL3 function in cell-cell adhesion, focusing on FMNL3¿s transit from intracellular storage sites to the plasma membrane, and activation at the plasma membrane during this process. Overall, this project will provide fundamentally novel mechanistic information on filopodial assembly, as well as providing novel molecular connections between actin dynamics and early events in cell-cell adhesion.
项目总结/文摘

项目成果

期刊论文数量(0)
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专利数量(0)

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HENRY N HIGGS其他文献

HENRY N HIGGS的其他文献

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{{ truncateString('HENRY N HIGGS', 18)}}的其他基金

Supplement - Linking actin cytoskeleton to membrane dynamics in mitochondrial fission
补充-将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来
  • 批准号:
    10387000
  • 财政年份:
    2017
  • 资助金额:
    $ 31.19万
  • 项目类别:
Linking actin cytoskeleton to membrane dynamics in mitochondrial fission
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来
  • 批准号:
    9276895
  • 财政年份:
    2017
  • 资助金额:
    $ 31.19万
  • 项目类别:
Linking actin cytoskeleton to membrane dynamics in mitochondrial fission
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来
  • 批准号:
    10004663
  • 财政年份:
    2017
  • 资助金额:
    $ 31.19万
  • 项目类别:
Linking actin cytoskeleton to membrane dynamics in mitochondrial fission - Undergrad Supplement
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来 - 本科生补充
  • 批准号:
    10591210
  • 财政年份:
    2017
  • 资助金额:
    $ 31.19万
  • 项目类别:
The impact of dynamic actin polymerization on mitochondrial dynamics and function
动态肌动蛋白聚合对线粒体动力学和功能的影响
  • 批准号:
    10405718
  • 财政年份:
    2017
  • 资助金额:
    $ 31.19万
  • 项目类别:
The impact of dynamic actin polymerization on mitochondrial dynamics and function
动态肌动蛋白聚合对线粒体动力学和功能的影响
  • 批准号:
    10670903
  • 财政年份:
    2017
  • 资助金额:
    $ 31.19万
  • 项目类别:
Linking actin cytoskeleton to membrane dynamics in mitochondrial fission
将肌动蛋白细胞骨架与线粒体裂变中的膜动力学联系起来
  • 批准号:
    10245015
  • 财政年份:
    2017
  • 资助金额:
    $ 31.19万
  • 项目类别:
Molecular Interactions and Imaging Core
分子相互作用和成像核心
  • 批准号:
    10460274
  • 财政年份:
    2016
  • 资助金额:
    $ 31.19万
  • 项目类别:
Molecular Interactions and Imaging Core
分子相互作用和成像核心
  • 批准号:
    10647704
  • 财政年份:
    2016
  • 资助金额:
    $ 31.19万
  • 项目类别:
Molecular Interactions and Imaging Core
分子相互作用和成像核心
  • 批准号:
    10271748
  • 财政年份:
    2016
  • 资助金额:
    $ 31.19万
  • 项目类别:

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