Kinase Control of Synergistic Cell Migration Mechanics

协同细胞迁移机制的激酶控制

• 批准号: 10797833
• 负责人: Michelle Christine Mendoza
• 金额: $ 6.65万
• 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/10797833
• 关键词: Actins; Adhesions; Basic Science; Biosensor; Cell Adhesion; Cell model; Cell physiology; Computer Models; Development; Disease; Foundations; Goals; Invaded; Malignant Neoplasms; Measures; Mechanics; Membrane; Molecular; Motion; Mutation; Neoplasm Metastasis; Output; Pathologic; Pattern; Phosphotransferases; Process; Protein Kinase; Public Health; Regulation; Research; Role; Signal Pathway; Signal Transduction; Testing; Traction; Width; Work; ZYX gene; cancer cell; cell motility; ezrin; improved; innovation; migration; novel therapeutic intervention; optogenetics; permissiveness; prevent; scaffold; spatiotemporal; 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 细胞迁移是发育所必需的基本细胞过程，在诸如 癌症转移。我们的长期目标是阐明控制迁移和癌症侵袭的信号，所以 可以改进减少病理性转移和癌症转移的治疗策略。波动 在细胞迁移中，力控制前沿突起-收缩循环，但我们不知道是什么控制了 力的波动。这里的总体目标是了解控制和整合的信号机制 细胞迁移的波动分子作用力。信号通路可以通过引导空间定位的和 肌动蛋白、黏附和膜张力参数的协调波动(指导性)。或者， 信号通路可能会指示一些过程，并在其他过程中起不到时空精确度(允许)的作用。 我们将通过解剖细胞迁移的时间和空间调节来阐明细胞迁移控制的机制。 蛋白激酶ERK及其在未转化细胞和癌细胞中的信号输出。ERK在多个步骤中发挥作用 凸出-回缩循环。与疾病相关的癌细胞模拟了一种高活性状态，在这种状态下，ERK 由于致癌基因突变，活性被上调。我们的中心假设是ERK在空间上指导- 边缘运动的肌动蛋白组装、黏附寿命和膜张力的局部协同波动 和细胞迁移。对于第一个目标，我们将测量EDGE期间ERK活动的时间波动 使用改良的ERK生物传感器进行突起和回缩。我们将把实验观察到的 将活动波动转化为计算模型和实验测试，以确定哪些模式决定 突出速度和持久性。对于第二个目标，我们将确定空间组织的ERK活动 控制边运动。我们将测试膜和黏附激活的ERK诱导突起的能力 无论是在实验上还是在计算上。我们还将测试ERK在膜上的滞留模式和 粘连结构域对突起功率和宽度有贡献。对于第三个目标，我们将测试ERK是否是控制 膜张力和粘着寿命对挤出速度的影响。我们将通过Zysin和Ezrin测试信令 将肌动蛋白作为ERK控制这些额外分子作用力的可能机制。建议数 这项研究在概念上是创新的，因为它测试了波动的ERK信号在细胞调控中的作用 迁移。它在开发和使用新的光遗传学工具和计算方面具有技术创新 模特们。这项研究意义重大，因为它有可能揭示一种关于分子如何 力量被整合起来，以产生运动。它还将识别控制局部ERK活动的支架和信号 可适应新的治疗策略的波动，以控制细胞黏附和迁移。