Kinase Control of Synergistic Cell Migration Mechanics

协同细胞迁移机制的激酶控制

• 批准号: 10446072
• 负责人: Michelle Christine Mendoza
• 金额: $ 30.7万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-10 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446072
• 关键词: Actins; Acute; Adhesions; Basic Science; Binding; Biology; Biosensor; Bundling; Carcinoma; Cell Adhesion; Cell membrane; Cell model; Cell physiology; Cells; Collagen; Computer Models; Coupled; Data; Development; Disease; Epithelial Cells; Foundations; Gel; Goals; Image; Individual; Instruction; Integrins; Knowledge; Lighting; Location; MAP3K1 gene; MEKs; Malignant Neoplasms; Measurement; Measures; Mechanics; Mediating; Membrane; Migration Assay; Modeling; Molecular; Motion; Mutation; Neoplasm Metastasis; Oncogenes; Output; Pathologic; Pattern; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Process; Protein Kinase; Proteins; Public Health; Receptor Activation; Receptor Protein-Tyrosine Kinases; Regulation; Relaxation; Research; Role; Signal Pathway; Signal Transduction; Site; Testing; Traction; Width; Work; ZYX gene; base; cancer cell; cell motility; ezrin; improved; innovation; migration; mutant; novel therapeutic intervention; optogenetics; polymerization; prevent; recruit; scaffold; spatiotemporal; therapeutic target; time use; tool; treatment strategy; wound healing

Project Abstract Cell migration is a fundamental cellular process necessary for development and coopted in diseases like cancer metastasis. Our long-term goal is to elucidate the signals that control migration and cancer invasion, so that treatment strategies to reduce pathological migration and cancer metastasis can be improved. Fluctuations in cell migration forces control leading edge protrusion-retraction cycles, but we do not know what controls the force fluctuations. The overall objective here is to understand the signaling mechanisms that control and integrate the fluctuating molecular forces of cell migration. Signaling pathways can act by directing spatially-localized and coordinated fluctuations in actin, adhesion, and membrane tension paramters (instructive). Alternatively, signaling pathways may instruct some processes and act without spatiotemporal precision (permissive) in others. We will elucidate the cell migration control mechanisms by dissecting the temporal and spatial regulation of the protein kinase ERK and its signaling outputs in untransformed and cancer cells. ERK acts on multiple steps in the protrusion-retraction cycle. The disease-relevant cancer cells model a high-activity state, in which ERK activity is upregulated due to onocogenic mutations. Our central hypothesis is that ERK instructs spatially- localized synergistic fluctuations in actin assembly, adhesion lifetime, and membrane tension for edge motion and cell migration. For the first aim, we will measure the temporal fluctuations in ERK activity during edge protrusion and retraction using modified ERK biosensors. We will incorporate the experimentally-observed activity fluctuations into a computational model and experimental tests to determine which patterns dictate protrusion velocity and persistence. For the second aim, we will determine if spatiatially-organized ERK activity controls edge motion. We will test membrane and adhesion-activated ERK for the ability to induce protrusion experimentally and computationally. We will also test how the pattern of ERK retention in the membrane and adhesion domains contributes to protrusion power and width. For the third aim, we will test if ERK is controls membrane tension and adhesion lifetime for protrusion velocity. We will test signaling through Zyxin and Ezrin to actin as possible mechanisms by which ERK controls these additional for molecular forces. The proposed research is conceptually innovative because it tests the role of fluctuating ERK signals in the regulation of cell migration. It is technically innovative in the development and use of new optogenetics tools and computational models. The research is significant because it has the potential to reveal a new principle about how molecular forces are integrated to bring about motion. It will also identify scaffolds and signals that control local ERK activity fluctuations that could be adapted for new therapeutic strategies to control cell adhesion and migration.

项目摘要 细胞迁移是开发和在诸如疾病中使用的基本细胞过程 癌症转移。我们的长期目标是阐明控制迁移和癌症入侵的信号，因此 可以改善减少病理迁移和癌症转移的治疗策略。波动 在细胞迁移力中控制前缘突出 - 撤退循环，但我们不知道是什么控制 力波动。这里的总体目的是了解控制和集成的信号传导机制 细胞迁移的分子力波动。信号通路可以通过指导空间定位和 肌动蛋白，粘附和膜张力参数（启发性）中的协调波动。或者， 信号通路可以指导某些过程并在其他过程中无时无时空精度（允许）起作用。 我们将通过剖析细胞迁移控制机制来阐明细胞迁移控制机制 蛋白激酶ERK及其信号传导在未转化和癌细胞中输出。 ERK采取多个步骤 突出 - 撤离周期。与疾病相关的癌细胞对高活动状态进行了模拟，其中ERK 由于致病性突变，活动被上调。我们的中心假设是ERK在空间上指导 肌动蛋白组装，粘附寿命和边缘运动的膜张力中的局部协同波动 和细胞迁移。为了第一个目标，我们将测量边缘ERK活动中的时间波动 使用改良的ERK生物传感器的突出和缩回。我们将合并实验性观察 活动波动到计算模型和实验测试，以确定哪些模式决定了 突出速度和持久性。对于第二个目标，我们将确定是否存在空间组织的ERK活动 控制边缘运动。我们将测试膜和粘附激活的ERK，以诱导突出 实验和计算。我们还将测试如何在膜上保留ERK的模式以及 粘附域有助于突出能力和宽度。对于第三个目标，我们将测试ERK是否为控件 膜张力和粘附寿命的突出速度。我们将通过Zyxin和Ezrin测试信号传导 肌动蛋白作为可能的机制，通过ERK控制这些额外的分子力。提议 研究在概念上具有创新性，因为它测试了ERK信号在细胞调节中的作用 迁移。它在开发和使用新的光遗传学工具和计算方面具有创新性 型号。这项研究很重要，因为它有可能揭示有关分子如何的新原理 部队被整合以实现运动。它还将确定控制本地ERK活动的脚手架和信号 可以适应新的治疗策略来控制细胞粘附和迁移的波动。