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：
10249352
负责人：
Martha C Soto
金额：
$ 33.96万
依托单位：
RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
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/10249352
关键词：
Actins Address Adhesions Affect Animal Model 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 Epithelial F-Actin Fragile X Syndrome Genes 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 base blastomere structure cell motility clinically relevant developmental disease experimental study extracellular gastrulation genetic approach human disease insight malignant breast neoplasm membrane model migration mutant neurodevelopment neuron development novel polarized cell protein degradation receptor recruit trafficking 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概要/摘要细胞外信号通过质膜上的受体发挥作用的过程影响细胞功能是生命的基本要求。细胞骨架元素，包括分支肌动蛋白，在整个细胞内传输信号。当分支肌动蛋白不正常时极化这可能会导致严重的健康问题，例如神经元发育缺陷或癌症转移。我们研究肌动蛋白细胞骨架如何解释细胞外信号执行极化功能，包括极化细胞迁移和极化细胞内贩运。我们建立了一个适合基因的系统，其中向特定的信号发送信号可以分析组织。我们的系统还识别促进特定的相关信号发育过程，揭示了有助于传播的新成分信号，并使用实时成像来深入了解信号控制的细胞生物学。之前我们识别并表征了膜募集模式的三个信号 GTPase Rac1/CED-10，进而招募分支肌动蛋白调节因子 WAVE/Scar 调节细胞迁移过程中 F-肌动蛋白的动态。现在我们准备好解决： 1) 分支肌动蛋白如何促进钙粘蛋白运输，从而建立适当的顶端/基底极性？ 2) 哪些 Rac GEF 特异性地将表皮接收到的信号转化为表皮运动线索？ 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：我们研究的基因之一的人类同源物线虫中的 WAVE3 被认为是高级三阴性乳腺癌的生物标志物癌症（Kulkarni et al., 2012）并与侵袭性前列腺癌和结肠癌相关（Fernando 等人，2010；Zhang 等人，2012）。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。