SPATIAL CONTROL OF INTRACELLULAR SIGNALING (Lee Bardwell, Theme Leader) | Some of the greatest mysteries in biological spafial dynamics lie at the subcellular level. The successes of biochemical and reconstitution-based assays in explaining fundamental mechanisms of cell biology have madeit easy to lose sight of the fact that cells are not just bags of well-sfirred enzymes. With respect to intracellular signaling pathways, there is growing evidence that spatial control is crucial to normal function [192-194] and occurs at many scales: compartments (plasma memtjrane, nucleus); sub-compartments (e.g. membrane rafts and nuclear speckles) and, below these levels, the nano-spafial scale, defined by local tethering interactions. Such spatial regulation is necessarily dynamic: scaffold proteins move to the plasma membrane, kinases and transcription factors move into or out of the nucleus, tethering interactions are regulated by phosphorylation, etc. In addifion, motor-based transport is used both to construct compartments, and to transport signaling molecules during sfimulafion; in turn this transport is regulated by extra- and intracellular cues. Yet for all the evidence that space matters, we often know less about spatial dynamics inside cells than outside of them. We propose three projects that deal with distinct,aspects of intracellular spatial dynamics, but are linked by their reliance on novel, cutting-edge optical, bioinformatic, and modeling methodologies. All three seek to open new lines of inquiry and, as such, incur more than a little technical risk. We believe the risks are justified by the expected gains in discovery and understanding in such a pooriy understood, yet extremely important, area.
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