New insights into extracellular signal transduction

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PROJECT SUMMARY One of the most fundamental properties of cells is the ability to transduce signals to other cells and the surrounding environment. Well recognized modes of cellular signaling include direct cell-cell interactions via membrane receptors and ligands and the release of soluble factors, such as growth factors, cytokines and chemokines. The more recently described extracellular vesicle (EV) is now also considered as an important mediator of cell signaling, allowing cells to exchange proteins, lipids and genetic material. EVs are secreted from nearly all cell types and EV-based communication relies on the ability of vesicles to deliver bioactive molecules to other cells. The field of EV biology is rapidly evolving and expanding, affecting almost all biomedical disciplines, from oncology and obstetrics to infectious diseases and stem cell biology. Cells release EVs not only in culture but also in vivo, and diverse types of vesicles have been isolated and analyzed from almost all bodily fluids, leading to the postulation that EV-based liquid biopsies can be used for diagnostics. However, despite the excitement and hundreds of new publications on EVs in recent past, several basic hypotheses regarding their function remain experimentally untested. A major challenge in EV research is the huge and often underappreciated diversity in shed vesicles. Many of the impediments to advance EV biology and application, stem from the inability to separate a complex population of vesicles into subclasses of particular sizes, compositions, and biogenesis pathways. Microvesicles (MVs) are an EV subtype which are shed by the direct outward budding of the plasma membrane. They are present in biological fluids and appear to be involved in multiple physiological and pathological processes. However, much remains unknown regarding the biogenesis and role of these vesicles as signaling mediators. Here we propose strategies to catalog molecular cargoes targeted specifically to MVs and identify new regulators of cargo loading. We also aim to interrogate GTPase-regulated cell signaling pathways that regulate MV release. Finally, we will examine the interactions of MVs with receptors on endothelial cells and consequent signaling pathways activated in the recipient cell. These studies will provide new insights into a rapidly evolving frontier in signal transduction, as well as the molecular basis of various diseases.