Dissecting the role of formins in large-scale endocytosis
剖析福尔明在大规模内吞作用中的作用
基本信息
- 批准号:419912200
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2019
- 资助国家:德国
- 起止时间:2018-12-31 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Phagocytosis and macropinocytosis are closely related and evolutionary conserved clathrin-independent endocytic processes. Both are actin-driven processes downstream of Ras and Rac signaling that entail rearrangements of the plasma membrane to engulf extracellular material followed by delivery of the ingested material into lysosomes for extraction of nutrients. However, the regulatory mechanisms underlying actin assembly in large-scale endocytosis still remain elusive. This project aims to clarify the specific contribution of formin family members to both macropinocytosis and phagocytosis, and elucidate their prospective synergy to each other and with the Arp2/3 complex in actin assembly during large-scale endocytosis downstream of Ras and Rac signalling. In previously published work, we established that the Diaphanous-related formin ForG is regulated by RasB and RasG and that it exhibits rather poor nucleation but effective actin-filament elongation activities. ForG contributes to the generation of actin filaments localized at the cup base and its activity is required for the generation of about 50% of the actin filaments in this structure. Since the Arp2/3 complex is apparently activated only at the expanding rims of the cups, it remains currently unclear which factors are at play that are responsible for the synthesis of the other half of the actin filaments in the base as well as for the filaments closer to the rim. Previous studies with fluorescently tagged biosensors in fact revealed that the entire periphery is decorated with active Rac, suggesting the presence of other factors than the Rac-binding Scar/WAVE complex, which appears to be required activating Arp2/3 complex in the tips. Of note, with ForB we have recently identified a second Diaphanous-related formin that prominently accumulates in its active form at the entire periphery of macropinosomes. Since this type of formins is in most cases activated by Rho-family GTPase members and because all other Dictyostelium formins that are expressed during the growth phase can be functionally excluded, we hypothesize that ForB could be the missing factor which is required together with ForG for the assembly of the majority of actin filaments in endocytic cups. The dissection of formin function in large-scale endocytosis is undoubtedly a challenging task, but we anticipate that by using various complementary approaches including thorough biochemical analysis of ForB, the identification of its regulatory Rac protein as well as the comprehensive cell biological analyses of single- and double-knockout cell lines as specified in the work programme will finally reveal the molecular activities and mechanisms underlying regulation of actin assembly in these large endocytic structures.
吞噬作用和巨胞饮作用是密切相关的,并且是进化上保守的不依赖网格蛋白的内吞过程。两者都是Ras和Rac信号传导下游的肌动蛋白驱动的过程,其需要质膜重排以吞噬细胞外物质,然后将摄入的物质递送到溶酶体中以提取营养物。然而,大规模内吞作用中肌动蛋白组装的调控机制仍然是难以捉摸的。该项目旨在阐明巨胞饮和吞噬作用的具体贡献,并阐明其相互之间以及与Ras和Rac信号下游大规模内吞作用中肌动蛋白组装中Arp 2/3复合物的协同作用。在以前发表的工作中,我们建立了半透明相关的RasB和RasG调节,它表现出相当差的成核,但有效的肌动蛋白丝伸长活动。ForG有助于产生定位在杯基部的肌动蛋白丝,并且其活性是产生该结构中约50%的肌动蛋白丝所需的。由于Arp 2/3复合物显然只在杯状突起的扩张边缘被激活,目前还不清楚是哪些因素在起作用,这些因素负责基底中另一半肌动蛋白丝的合成以及更靠近边缘的细丝的合成。事实上,先前使用荧光标记的生物传感器的研究显示,整个外周都装饰有活性Rac,这表明除了Rac结合的Scar/WAVE复合物之外,还存在其他因素,这似乎需要激活尖端中的Arp 2/3复合物。值得注意的是,与ForB,我们最近发现了第二个透明相关的蛋白质,显着积累在其活性形式在整个周边的macropinosomes。由于这种类型的formins在大多数情况下是由Rho家族GT3成员激活的,并且因为在生长阶段表达的所有其他Dictyosteoblasts formins可以在功能上被排除在外,我们假设ForB可能是缺失的因子,该因子与ForG一起用于内吞杯中大多数肌动蛋白丝的组装。大规模内吞作用中ForB功能的剖析无疑是一项具有挑战性的任务,但我们预计,通过使用各种互补方法,包括对ForB进行彻底的生化分析,其调节Rac蛋白的鉴定以及单和双-工作计划中规定的敲除细胞系将最终揭示这些大细胞中肌动蛋白组装调控的分子活性和机制。内吞结构
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Professor Dr. Jan Faix其他文献
Professor Dr. Jan Faix的其他文献
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{{ truncateString('Professor Dr. Jan Faix', 18)}}的其他基金
Ena/VASP proteins in cell motility and adhesion
Ena/VASP 蛋白在细胞运动和粘附中的作用
- 批准号:
264240917 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Research Grants
Relating specific biochemical activities of ADF/cofilin family members to their physiological functions
将 ADF/cofilin 家族成员的特定生化活性与其生理功能联系起来
- 批准号:
238964129 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Priority Programmes
Dissecting the role of I-BAR proteins in VASP clustering and actin assembly
剖析 I-BAR 蛋白在 VASP 聚类和肌动蛋白组装中的作用
- 批准号:
234826310 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Research Grants
Dissection of formin pathways coordinating polarity with cell migration downstream of Ras signalling
福尔明通路的剖析,协调极性与 Ras 信号下游细胞迁移
- 批准号:
169554986 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Priority Programmes
Novel roles of SCAR/WAVE subunits in the regulation of actin dynamics
SCAR/WAVE 亚基在肌动蛋白动力学调节中的新作用
- 批准号:
157539715 - 财政年份:2009
- 资助金额:
-- - 项目类别:
Research Grants
Characterization of the molecular interplay between VASP, formins and their accessory proteins during filopodium formation
丝状足形成过程中 VASP、福明及其辅助蛋白之间分子相互作用的表征
- 批准号:
22176014 - 财政年份:2006
- 资助金额:
-- - 项目类别:
Research Units
Function of cortical formins in the motility of strongly adherent cells
皮质形式在强贴壁细胞运动中的功能
- 批准号:
321587294 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Grants
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