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Rewiring Eukaryotic Signaling Networks using Synthetic Posttranslational Connections

  • Author(s): Williams, Reid Edward
  • Advisor(s): Lim, Wendell A
  • et al.
Abstract

Cells are dynamic, adaptive structures--able to sense their environment and change their behavior accordingly. This ability is largely driven by signaling pathways--networks of interconnected proteins and genes that sense environmental conditions and process this information to effect specific phenotypes through changes in gene-expression or protein activity. A major challenge in understanding how cells respond to their environment is

to understand how the connections (or wiring) of signaling proteins determines network function. Here, several tools are engineered that allow novel regulatory connections to be made between proteins in a mitogen activated protein (MAP) kinase network. Specifical- ly, these tools allow phosphorylation of a MAPK protein to be converted to degradation or to changes in nuclear / cytoplasmic localization of an arbitrary protein. These tools are then applied to (1) build a posttranslational positive feedback loop that alters the dynamic behavior of the Saccharomyces cerevisiae mating pathway, and (2) to tune the behavior of an existing gene-expression based bistable circuit to be more sensitive to the duration of input stimulus required to switch the circuit from one stable state to another. Computational modeling suggests that the addition of posttranslational feedback (positive or negative) is a general scheme by which an existing gene-expression based bistable circuit can be tuned to be more or less sensitive to the duration of input required to switch from one state to another.

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