Prostaglandins and actin remodeling

点击翻译按钮获取中文摘要

All eukaryotic cells produce and respond to prostaglandin (PG) signaling. PGs are lipid signaling molecules that have a wide range of functions from inflammation to fertility to wound healing. Imbalances in PG signaling underly many diseases, such as birth defects, cardiovascular disease, and cancer. PGs have such wide effects because there are 5 types of PGs, and each activates multiple signaling cascades. All PGs are produced by a multistep process that requires cyclooxygenase (COX) enzymes. COX enzymes are the targets of the commonly used non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin and ibuprofen. Thus, NSAIDs block all PG synthesis and signaling. To develop more specific therapies and to better understand the functions of PGs, it is essential to uncover the cellular roles of PG signaling. One understudied cellular function of PGs is to regulate actin remodeling to promote collective cell migration. While over 50,000 studies have uncovered critical regulators of cell migration, less than 60 studies have focused on the roles of PGs in this process. Thus, how PGs regulate actin remodeling and migration remains elusive. The roles of individual PG signaling pathways, and whether they act in the migratory cells or their substrate to coordinate cell migration are poorly understood. Further, the specific actin regulators that are the downstream effectors of PG signaling, and how they are modulated, are largely unknown. To overcome these knowledge gaps, we take advantage of the robust system of Drosophila and the in vivo, collective migration of the border cells during oogenesis. In the last five years, we found that PG synthesis in the border cells promotes on-time migration, whereas PG synthesis in the substrate controls border cell cluster cohesion. We identified that one downstream target of PGs in both the border cells and their substrate is Fascin. In addition to bundling actin, we found Fascin regulates the transmission of force to the nucleus by promoting the activity of the Linker of the Nucleoskeleton and Cytoskeleton (LINC) Complex, and the transmission of force between cells by inhibiting myosin. Using genetic, cellular, biochemical, and biophysical approaches, the proposed studies are expected to build a new paradigm for how PG signaling, and its effects on Fascin, coordinate the behaviors of migrating cells and their cellular substrates to promote collective cell migration. We propose to address: 1) Which PG signaling cascades act in the migratory cells versus their substrate to regulate collective cell migration? 2) How does PG signaling regulate Fascin? 3) What is the role of PG signaling in LINC Complex-mediated mechanotransduction during migration? 4) How does PG signaling control the balance of forces between the migratory cells and their substrate during collective cell migration? Through this work, we expect to fundamentally advance our mechanistic understanding of how multiple PG signaling pathways and Fascin mediate force transmission both inside cells to control nuclear dynamics and within tissues to control collective migration. This increased understanding can be applied to develop novel therapeutics to prevent/treat birth defects, wound healing complications, and cancer metastasis.