CAREER: Small-Molecule-Regulated Signaling Proteins

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This award in the Chemistry of Life Processes program of the Chemistry Division is co-funded by the Cell cluster in the Division of Molecular and Cellular Biosciences. The award supports work by Professor Dustin Maly at the University of Washington in Seattle to engineer mammalian signaling enzymes that can be regulated with cell-permeable small molecules. Conversion of external stimuli into complex cellular behaviors is mediated by networks of interacting multi-domain signaling enzymes. The use of engineered signaling enzymes that can be controlled in a rapid, reversible and dose-dependent manner with small molecules in living cells allows the roles of individual proteins and proteins domains in specific signaling events to be determined. Uncovering the roles and contributions of components in these networks provides insight into aberrant cellular phenotypes and facilitates efforts to rationally engineer cells with novel behaviors. The interdisciplinary nature of this research allows the participation of undergraduate and graduate students with diverse scientific interests. Furthermore, this research program serves as a vital scientific link between the University of Washington and local area high schools that contain large populations of disadvantaged and under-represented students. External information is converted into complex cellular behaviors such as growth, differentiation and motility by networks of signaling enzymes. By re-engineering signaling enzymes from simple modules and observing the effects of these synthetic proteins on cellular behavior, it will be possible to uncover the core design principles behind complex biological systems. Determining the roles and contributions of the proteins involved in specific signaling events provides an understanding of the molecular wiring of cells. Furthermore, determining the logic of signal transduction networks facilitates the rational engineering of cells with unique phenotypic behaviors.