Control of cell polarity and migration by non-centrosomal microtubules
非中心体微管控制细胞极性和迁移
基本信息
- 批准号:10046568
- 负责人:
- 金额:$ 16.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2022-05-31
- 项目状态:已结题
- 来源:
- 关键词:ActinsActomyosinAddressAffectArchitectureBinding ProteinsBiological ProcessBlood VesselsCalmodulinCell PolarityCell ShapeCellsCentromereCentrosomeComplementComplexCuesCytoskeletal ProteinsCytoskeletonDataDestinationsDevelopmentDevelopmental ProcessDiseaseEndothelial CellsEnzymesEpithelial CellsFamilyFluorescence MicroscopyFocal AdhesionsFutureGrowthGuanosine Triphosphate PhosphohydrolasesHealthHeart DiseasesHeart NeoplasmsInvestigationKinesinKnowledgeLabelLifeLinkMaintenanceMeasuresMediatingMicrofilamentsMicroscopyMicrotubule DepolymerizationMicrotubule-Associated ProteinsMicrotubulesMinus End of the MicrotubuleMitoticMolecular MotorsMonomeric GTP-Binding ProteinsMovementMyosin ATPaseMyosin Type IINeoplasm MetastasisOutcomePeripheralPlus End of the MicrotubuleProcessProtein FamilyProteinsPublishingRegulationResearch DesignResearch PersonnelResearch ProposalsResolutionRoleSignal TransductionSignaling MoleculeSignaling ProteinSpectrinStress FibersSystemTestingTimeTotal Internal Reflection FluorescentTractionWorkcell motilitydirectional cellgenetic approachknock-downlive cell imagingmigrationoverexpressionpolarized cellresponsetumorundergraduate studentwound healing
项目摘要
Project Summary/Abstract
The coordinated and regulated remodeling of the actin and microtubule (MT) cytoskeleton is required for cell migration
for developmental processes and homeostatic maintenance, as well as during the body’s response to external insults and
disease states including heart disease and tumor metastasis. During cell migration, actin filaments assemble and become
linked to focal adhesion (FA) complexes, while MTs undergo dynamic instability that is locally controlled by MT-
associated proteins (MAPs). These two processes enable cells to establish a leading-edge and a trailing-edge, and to
migrate with directional persistence. Despite many advances in our understanding of the functional implications of MAPs
on MTs and MT-FA interactions, it remains unknown how exactly MT organization is spatially and temporally
coordinated with FAs to promote directional cell movement. A recent discovery showing that non-centrosomal MTs are
both sufficient and required to drive polarized cell migration has established a paradigm shift, suggesting that non-
centrosomal MTs are primed to function in a way that is distinct from MTs nucleated by the centrosome. The finding
underscores the need to determine how cytoskeletal proteins identify and regulate non-centrosomal versus centrosomal
MT dynamics and effects on polarity and migration. This gap in knowledge impacts our understanding of fundamental
processes, including how signaling molecules simultaneously regulate families of proteins to achieve complex tasks, such
as guiding persistent cell migration. The small GTPase, Rac1, is a key signaling protein that is spatially controlled to
promote FA formation, MT growth, and actin filament assembly, resulting in leading edge advance. Rac1 signaling is
complemented by the molecular motor protein, myosin-II, which organizes actin stress fibers, promotes FA maturation,
and generates forces that pull the trailing-edge of the cell forward. Thus, Rac1 and myosin-II are spatially and temporally
controlled to drive directional cell movement. One targeted MT effector protein, MCAK, is locally inhibited by Rac1 to
promote leading-edge MT growth and cell polarity, and MCAKs effects on MT dynamics are sensitive to myosin-II
contractility. Despite this knowledge, how Rac1 and myosin-II contribute to the organization of FAs, MTs, and actin is
not well understood. Preliminary evidence demonstrates that FA-associated MTs are predominantly of non-centrosomal
origin and that Rac1 activity enhances the association of two different families of MAPs, CAMSAPs and septins, which
increase non-centrosomal MT growth into FAs. Here, we will test the hypothesis that Rac1 and myosin-II promote the
association of CAMSAP and septins with non-centrosomal MTs, which inhibits MCAK-mediated MT disassembly and
drives MT-FA interactions. Our approach will incorporate a team of undergraduate researchers using fluorescence
microscopy of live endothelial cells to determine: (1) how Rac1 and myosin-II regulate CAMSAP and septin interactions
with non-centrosomal MTs, (2) how MCAK disassembly of non-centrosomal MTs controls MT dynamics and FA size,
and (3) how septins promote MT growth into FAs. These investigations will provide critical advances to the field of cell
migration by functionally linking Rac1 and myosin-II with cytoskeletal effector proteins that control non-centrosomal MT
growth into FAs and the regulation of cell migration in health and disease.
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项目总结/摘要
细胞迁移需要肌动蛋白和微管(MT)细胞骨架的协调和调节重塑
对于发育过程和稳态维持,以及在身体对外部侮辱的反应期间,
疾病状态,包括心脏病和肿瘤转移。在细胞迁移过程中,肌动蛋白丝组装成
与粘着斑(FA)复合物连接,而MT经历由MT局部控制的动态不稳定性。
相关蛋白(MAPs)。这两个过程使细胞能够建立前沿和后沿,
以定向持久性迁移。尽管我们对MAP的功能意义的理解取得了许多进展,
关于MT和MT-FA相互作用,MT组织在空间和时间上的精确程度仍然未知
与FA协调以促进定向细胞运动。最近的一项发现表明,非中心体MT是
已经建立了一个范式转变,这表明非极化细胞迁移是足够的,也是必需的。
中心体MT被引发以不同于由中心体成核的MT的方式发挥功能。这一发现
强调需要确定细胞骨架蛋白如何识别和调节非中心体与中心体
MT动力学及其对极性和迁移的影响。这种知识上的差距影响了我们对基础知识的理解。
过程,包括信号分子如何同时调节蛋白质家族以实现复杂的任务,
引导持续的细胞迁移。小的GTdR,Rac 1,是一种关键的信号蛋白,在空间上受到控制,
促进FA形成、MT生长和肌动蛋白丝组装,导致前缘前移。Rac 1信号是
由分子马达蛋白肌球蛋白II补充,肌球蛋白II组织肌动蛋白应力纤维,促进FA成熟,
并产生向前拉电池后缘的力。因此,Rac 1和肌球蛋白-II在空间和时间上是相互关联的。
控制细胞定向运动。一种靶向MT效应蛋白MCAK被Rac 1局部抑制,
促进MT前沿生长和细胞极性,MCAKs对MT动力学的影响对肌球蛋白II敏感
收缩性尽管有这些知识,Rac 1和肌球蛋白-II如何促进FA,MT和肌动蛋白的组织仍是未知的。
没有很好地理解。初步证据表明,FA相关的MT主要是非中心体的
Rac 1活性增强了两个不同的MAP家族CAMSAP和septins的结合,
增加非中心体MT向FA生长。在这里,我们将测试Rac 1和肌球蛋白-II促进细胞增殖的假设。
CAMSAP和septins与非中心体MT的关联,其抑制MCAK介导的MT分解,
驱动MT-FA交互。我们的方法将包括一个本科研究人员团队,
活内皮细胞的显微镜检查,以确定:(1)Rac 1和肌球蛋白-II如何调节CAMSAP和septin相互作用
与非中心体MT,(2)非中心体MT的MCAK分解如何控制MT动力学和FA大小,
以及(3)septins如何促进MT生长为FA。这些研究将为细胞生物学领域提供重要的进展。
通过将Rac 1和肌球蛋白-II与控制非中心体MT的细胞骨架效应蛋白功能性连接而实现迁移
生长成脂肪酸和调节细胞迁移的健康和疾病。
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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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Kenneth Albert Myers其他文献
Kenneth Albert Myers的其他文献
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{{ truncateString('Kenneth Albert Myers', 18)}}的其他基金
Control of cell polarity and migration by non-centrosomal microtubules
非中心体微管控制细胞极性和迁移
- 批准号:
10470546 - 财政年份:2020
- 资助金额:
$ 16.46万 - 项目类别:
Control of cell polarity and migration by non-centrosomal microtubules
非中心体微管控制细胞极性和迁移
- 批准号:
10655684 - 财政年份:2020
- 资助金额:
$ 16.46万 - 项目类别:
Control of cell polarity and migration by non-centrosomal microtubules
非中心体微管控制细胞极性和迁移
- 批准号:
10630582 - 财政年份:2020
- 资助金额:
$ 16.46万 - 项目类别:
Regulation of Endothelial Cell Branching Morphogenesis via MCAK-targted Control
通过 MCAK 靶向控制调节内皮细胞分支形态发生
- 批准号:
8734610 - 财政年份:2013
- 资助金额:
$ 16.46万 - 项目类别:
Regulation of Endothelial Cell Branching Morphogenesis via MCAK-targted Control
通过 MCAK 靶向控制调节内皮细胞分支形态发生
- 批准号:
8739669 - 财政年份:2013
- 资助金额:
$ 16.46万 - 项目类别:
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