Molecular mechanisms initiating cell migrations in Caonorhabditis elegans

启动细胞迁移的分子机制 项目摘要/摘要 细胞外信号通过质膜上的受体作用于细胞外的过程 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，在整个细胞内传递信号。当分支肌动蛋白不正确时 两极分化会导致严重的健康问题，如神经元发育缺陷或 癌症转移。我们研究了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 贩卖人口。我们建立了一个遗传顺从系统，在这个系统中，信号转导到特定的 可以对组织进行分析。我们的系统还识别出促进特定目标的相关信号 发展过程，揭示了有助于繁殖的新组件 信号，并使用实时成像提供对信号控制的细胞生物学的洞察。 在此之前，我们识别和表征了三种膜募集的信号 GTPase rac1/CED-10，进而招募分支肌动蛋白调节因子WAVE/SCAR 来调节细胞迁移过程中F-肌动蛋白的动态。现在，我们准备解决以下问题： 1)分支肌动蛋白如何促进钙粘连蛋白运输建立适当的尖端/底端 极性？2)RAC环境基金(S)专门将表皮接收的信号转换为 表皮运动暗示？3)分支肌动蛋白依赖的黏附如何支持组织- 组织运动？临床相关性：我们研究的一种基因的人类同源物 在线虫中，WAVE3被认为是高级别、三重阴性乳房的生物标志物 癌症(Kulkarni等人，2012)，与浸润性前列腺癌和结肠癌有关 (Fernando等人，2010；Zhang等人，2012)。了解调节肌动蛋白的信号 在细胞迁移过程中通过波/疤痕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。

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.