Molecular Mechanisms of Cell Migration

细胞迁移的分子机制

基本信息

批准号：
10368936
负责人：
Catherine Green Galbraith
金额：
$ 31.81万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2025-03-31
项目状态：
未结题

项目摘要

Molecular Mechanisms of Cell Migration Project summary: Recognition of extracellular matrix (ECM) cues is critical to many developmental and homeostatic processes, and misinterpretation of cues underlies diseases such as metastasis. Cells probe for ECM cues by extending actin-based protrusions to bind ECM and form anchors to help them move forward. However, little is known about the decision processes and signaling pathways that convert ECM probing by protrusions into directed cell migration. Many conventional microscopy studies posit that protrusions are uniformly covered with randomly diffusing unbound ECM receptors that stochastically bind ECM. With our new approach of dense- field single molecule super-resolution microscopy, we have discovered a concentrated band of unbound ECM receptors at the front of protrusions that have characteristic molecular patterns of receptor organization, mobility, and functionalization. These patterns depend on both cellular protrusive activity and specific receptor cytoplasmic binding domains, indicating that cytoplasmic interactions, visible only at the single molecule level regulate how unbound integrins are organized in preparation for probing for ECM. In this proposal we will define the cellular decision processes that convert ECM probing into directed cell migration by integrating molecular measures of the organization, interaction, and functionalization of populations of ECM receptors with cellular measures of the assembly of adhesions, actin regulatory pathways, and protrusive activity. We will: 1) Define mechanisms that create the global spatial-temporal patterns of unbound ECM receptor organization, mobility, and conformation at the front of cell protrusions that regulate the functionalization of protrusions to probe ECM; 2) Identify signaling pathways that bound ECM receptors use to separate the decision to convert an ECM cue into directed migration from the decision to continue to probe the ECM through actin cytoskeletal dynamics. These studies will directly contribute to our understanding of cell recognition of ECM cues in many development and homeostasis processes, as well as our understanding of the misinterpretation of cues, which underlies diseases such as metastasis.

细胞迁移的分子机制项目摘要：识别细胞外基质（ECM）提示对于许多发育和稳态过程至关重要，以及对提示的误解是基于转移等疾病的基础。细胞通过扩展ECM提示的探测基于肌动蛋白的突起结合ECM并形成锚点，以帮助它们前进。但是，鲜为人知关于将突起探测到指示的决策过程和信号通路细胞迁移。许多常规显微镜研究认为，突起均匀地覆盖随机散布的未结合的ECM受体，它们随机结合ECM。随着我们新的密集方法场单分子超分辨率显微镜，我们发现了一个未结合的ECM的浓缩带具有受体组织特征性分子模式的突起的受体，移动性和功能化。这些模式取决于细胞突出活性和特定受体细胞质结合结构域，表明细胞质相互作用仅在单分子水平上可见调节未结合素的组织方式以准备探测ECM。在这个建议中，我们将定义通过集成将ECM探测为有向细胞迁移的细胞决策过程 ECM受体种群的组织，相互作用和功能化的分子测量粘附组装，肌动蛋白调节途径和突出活性的细胞测量。我们将：1）定义创建未结合ECM受体组织的全球空间周期模式的机制，迁移率和构象在细胞突起的前部调节突出的功能化探针ECM; 2）确定绑定ECM受体用来分开转换决定的信号通路 ECM提示从决定继续通过肌动蛋白细胞骨架探测ECM的决定迁移动力学。这些研究将直接有助于我们理解许多在许多人中对ECM提示的识别发展和稳态过程，以及我们对误解线索的理解，基础疾病（例如转移）。