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影响细胞的过程 功能是生活的基本要求。细胞骨架元件，包括分支肌动蛋白，传递信号 遍及整个细胞。当分支肌动蛋白没有正确极化时，这可能会导致严重的健康问题 比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 细胞内交易。我们建立了一种遗传顺从系统，在该系统中向特定组织发出信号 可以分析。我们的系统还识别促进特定发育的相关信号 处理，发现有助于信号传播的新组件，并使用实时成像来 提供对受信号控制的细胞生物学的洞察。在此之前，我们确定并描述了三个 GTPase rac1/CED-10的膜招募信号，进而招募分枝的 肌动蛋白调节器WAVE/SCAR在细胞迁移过程中调节F-肌动蛋白的动态。现在我们准备好了 地址：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)哪种RAC Global(S)专门将表皮接收到的信号转换为表皮运动性 线索？3)分支肌动蛋白依赖的黏附如何支持组织运动？临床 相关性：我们在线虫中研究的基因之一WAVE3的人类同源物被认为是 高级别、三阴性乳腺癌的生物标记物(Kulkarni等人，2012年)，并与侵袭性 前列腺癌和结肠癌(Fernando等人，2010；Zhang等人，2012)。理解调节的信号 细胞迁移过程中肌动蛋白通过波/疤痕复合体的动态变化将提示新的改变的生物标志物 肌动蛋白在人类疾病中的调控。

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 tissuetissue 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.