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.
/ Relevance of the Project to Public Health The regulators of branched actin are often mutated in various cancers and in diseases of neural development. These studies use a model organism, C. elegans, to address how branched actin is regulated for healthy development of properly polarized tissues. Therefore these studies will inform the causes of cancer and of neuronal developmental disease.
