New frontiers in extracellular signaling

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Abstract- The overall goals of our NIGMS-supported research have been to determine how EGF receptor (EGFR) family members and Rho GTPases trigger signaling pathways essential for normal biological processes and, when de-regulated, give rise to disease states. Our work has relied upon a combination of biochemical, cell biological, and structural approaches, as well as more recently, mouse models. These efforts led to our discovery of a novel signaling-pathway that results in the activation of a key metabolic enzyme, glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and is essential for highly proliferative cells including cancer cells. We then discovered that an important outcome of these metabolic changes is the generation of microvesicles (MVs), a specific subset of non-classical secretory vesicles that fall within the larger family of extracellular vesicles (EVs). MVs, together with the other major class of EVs, exosomes, are now garnering a great deal of attention because of their roles in a wide range of normal physiological processes as well as in different diseases. They have been linked to biological activities that span the evolutionary spectrum from bacteria to viral infectivity, and to a diversity of physiological processes in higher organisms including the immune response and neuronal function, as well as being connected to diseases such as cancer and neurodegenerative disorders. Moreover, EVs have also been implicated in stem cell biology, with our laboratory recently discovering that MVs shed from embryonic stem cells play a critical role in activating trophoblasts, an essential step in embryo implantation. Still, we are at an early stage in understanding the actions of these novel modes of information transfer between cells. In particular, there is a critical need to define the biochemical and signaling mechanisms that underlie MV functions. Among the important questions surrounding this exciting field include what are the signaling mechanisms responsible for the biogenesis of MVs by cancer cells where their actions have been most heavily studied, as well as the specific cues that dictate the loading of MVs with protein and RNA cargo, and whether they are conserved across different cell types. Moreover, we need to learn much more about the nature of the signals that trigger the shedding of MVs from their parental (donor) cells, thus enabling them to engage and transfer protein and RNA cargo to their target cells. Addressing these questions will require a number of new lines of research and development, as they represent an important and rapidly emerging frontier in signal transduction. Given our laboratory's experience and expertise, we are well positioned to define the signaling mechanisms responsible for the biogenesis and function of this novel form of intercellular communication, which ultimately should yield new insights into fundamentally important biological processes, as well as the molecular basis of various diseases and pathological disorders.