Studies of Global Signal Transduction

Abstract: Research in my laboratory has centered on the development and application of multi-disciplinary approaches to study signal transduction pathways important in normal physiology and, when de-regulated, contribute to a number of diseases. This began with our discovery and cloning of a novel signaling partner for

the epidermal growth factor receptor, the human Cdc42 protein, a small GTPase highly conserved from yeast to humans, and continued with the identification of many Cdc42 regulatory proteins and signaling targets. The conservation of Cdc42 throughout evolution accounts for the many fundamentally important roles it plays in cell

biology and organism development, including the regulation of cell growth and migration, and the establishment of cellular polarity. We then discovered an unanticipated but highly significant function of Cdc42 in directing the upregulation of glutamine metabolism and metabolic activities that generate building blocks for biosynthetic

processes required in a wide range of cellular functions. This also provides a mechanism for connecting the various intracellular processes regulated by Cdc42 to the surrounding environment by directing the biogenesis of extracellular vesicles (EVs), which have been implicated by our laboratory and others in mediating intercellular

communication across the evolutionary spectrum from bacteria to higher organisms. Recently, we found that Cdc42 activates these metabolic activities through the assembly of large protein complexes. Understanding how these metabolic/signaling nodes are assembled holds important clues to their regulation and function, as well as

sheds light on a long-standing question of how Cdc42 activates a critically important protein kinase, mTOR (mechanistic Target of Rapamycin), which is a necessary step for cap-dependent mRNA splicing, the neuronal differentiation of embryonic stem cells (ESCs), and the survival of cancer cells under stressful conditions.

Elucidating the biochemical and structural features of these large complexes that activate glutamine metabolism and mTOR, which are essential for cell growth and survival, and helping to move forward the field of EVs represent major research goals for our laboratory in the next 5-years. Key gaps in our knowledge surrounding

these broad areas of study will be addressed. We want to understand how Cdc42 directs the formation of metabolic/signaling nodes that not only play such important roles in cell biology but also have significant implications for disease, define the mechanisms responsible for their regulation, and determine their 3D

structures. We also will set out to address challenging questions to further the development of the EV field, by identifying the biochemical determinants and signaling cues that dictate the loading of essential EV cargo and determining the structural features of EVs that enable their various biological functions. To achieve these goals,

we will leverage our expertise in signal transduction and benefit from a strong group of collaborators.