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Molecular mechanisms initiating cell migrations in Caonorhabditis elegans

秀丽隐杆线虫细胞迁移的分子机制

基本信息

批准号：
10642919
负责人：
Martha C Soto
金额：
$ 33.96万
依托单位：
RUTGERS BIOMEDICAL AND HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10642919
关键词：
Actins Address Adhesions Affect Apical Biological Markers Cadherins Caenorhabditis elegans Cancer Etiology Cell Polarity Cell Surface Receptors Cell membrane Cell physiology Cell surface Cell-Cell Adhesion Cell-Matrix Junction Cells Cellular biology Cicatrix Colon Carcinoma Communication Complex Cues Cytoskeleton Development Developmental Process Disease E-Cadherin Elements Embryo Epidermis Epithelium F-Actin Fragile X Syndrome Genes Genetic Genetic Screening Grant Guanosine Triphosphate Phosphohydrolases Health Homologous Gene Human Image Individual Life Malignant Neoplasms Malignant neoplasm of prostate Membrane Mental Retardation Modeling Molecular Morphogenesis Movement Mutate Mutation Neoplasm Metastasis Neurons Pattern Process Public Health Regulation Role Schizophrenia Signal Transduction System Testing Time Tissue Model Tissues autism spectrum disorder cell motility clinically relevant developmental disease embryo cell experimental study extracellular gastrulation human disease insight malignant breast neoplasm membrane model migration model organism mutant neurodevelopment neuron development novel polarized cell protein degradation receptor recruit trafficking transmission process triple-negative invasive breast carcinoma

项目摘要

Molecular mechanisms initiating cell migrations Project Summary/Abstract The process by which extracellular signals act through receptors at the plasma membrane to influence cell function is a fundamental requirement for life. Cytoskeletal elements, including branched actin, transmit signals throughout the cell. When branched actin is not properly polarized this can result in serious health problems like defective neuronal development or cancer metastases. We study how the actin cytoskeleton interprets extracellular signals to carry out polarized functions, including polarized cell migrations and polarized intracellular trafficking. We established a genetically amenable system in which signaling to specific tissues can be analyzed. Our system also identifies the relevant signals that promote specific developmental processes, uncovers novel components contributing to the propagation of the signal, and uses live imaging to provide insights into the cell biology controlled by the signals. Previously we identified and characterized three signals that pattern membrane recruitment of the GTPase Rac1/CED-10, which in turn recruit the branched actin regulator WAVE/Scar to regulate the dynamics of F-actin during a cell migration. Now we are ready to address: 1) How does branched actin promote the Cadherin trafficking that sets up proper apical/basal polarity? 2) Which Rac GEF(s) specifically convert signals received by the epidermis into epidermal motility cues? 3) How does branched-actin-dependent adhesion support tissue- tissue movements? Clinical relevance: The human homolog of one of the genes we study in C. elegans, WAVE3, is considered a biomarker for high grade, triple negative breast cancer (Kulkarni et al., 2012) and is associated with invasive prostate and colon cancers (Fernando et al., 2010; Zhang et al., 2012). Understanding the signals that regulate actin dynamics through the WAVE/Scar complex during cell migrations will suggest new biomarkers for altered actin regulation in human disease.

启动细胞迁移的分子机制项目总结/摘要细胞外信号通过质膜上的受体作用，影响细胞功能是生命的基本要求。细胞骨架成分，包括分支肌动蛋白，在整个细胞中传递信号。当分支肌动蛋白不能正确地两极分化可能导致严重的健康问题，如神经元发育缺陷，癌症转移我们研究肌动蛋白细胞骨架如何解释细胞外信号，进行极化功能，包括极化细胞迁移和极化细胞内贩卖人口我们建立了一个遗传上可接受的系统，在这个系统中，可以分析组织。我们的系统还识别了促进特定发展过程中，发现新的组件有助于传播的信号，并使用实时成像提供信号控制的细胞生物学的见解。以前我们确定和表征了三种信号，模式膜招聘 GTCRac 1/CED-10的表达，进而募集分支肌动蛋白调节因子WAVE/Scar 来调节细胞迁移过程中F-肌动蛋白的动力学。现在，我们准备解决： 1)分支肌动蛋白如何促进钙粘蛋白的运输，建立适当的顶端/基底极性？2)哪些Rac GEF特异性地将表皮接收的信号转换为表皮运动线索3)分支肌动蛋白依赖性粘附如何支持组织- 组织运动临床相关性：我们研究的一个基因的人类同源物 in C.线虫，WAVE 3，被认为是高级别，三阴性乳腺癌的生物标志物，癌症（Kulkarni等人，2012），并与浸润性前列腺癌和结肠癌有关（Fernando等人，2010; Zhang等人，2012年）。了解调节肌动蛋白的信号细胞迁移过程中通过WAVE/Scar复合体的动力学将提示新的人类疾病中肌动蛋白调节改变的生物标志物。