We recently discovered a surprising class of dynamical behaviors in yeast signal transduction. Signaling transducers in Saccharomyces cerevisiae exhibit large stochastic bursts in their nuclear localizations, correspondingly in their phosphorylation dynamics, in the presence of constant amounts of signal. These pulses have typical duration of about a minute and are not synchronized in a population of genetically identical cells. Single cells measurements utilizing localization as an observable offer us a unique view of dynamics in post-translational modifications inside living cells. We have shown theoretically and confirmed experimentally that these bursts serve functional roles in coordinating downstream cellular networks. Furthermore, we found two other signaling pathways that exhibited similar but independent bursting behavior. These unexpected observations suggest that interesting dynamics in signal transduction exists for a significant subset of the proteome and plays significant functional roles that justify their existence over more gradual and less """"""""noisy"""""""" dynamics. Here, I propose a comprehensive interdisciplinary research program, by combining quantitative single-cell time-lapse microscopy with mathematical modeling, to obtain a system level understanding of the signal processing and decision making at the single cell level. Specifically, I plan to address the following questions: How much of the yeast proteome exhibits bursting in their localization dynamics? What are the mechanisms generating bursts and is there a common design principle? Finally, how does the cell process different signaling inputs and integrate them at the various levels of the pathway? My current postdoctoral training program, the Beckman Institute Fellowship at Caltech, provides a monthly meeting for me to exchange idea with the other Bl fellows in diverse scientific discipline from chemical engineering to behavioral neurobiology. The program is under the guidance of Prof. Barbara Wold, who provide additional guidance on scientific and career decision. The K award would allow me to use my remaining time as a postdoc to initiate experiments that will carry into my faculty years in a major research institution. Relevance: Signaling and coordination are critical to eukaryotic cells for decision making in diverse context. Imbalances in signals often results in diseases, such as cancer. We discovered a novel mode of signaling, akin to FM in radio broadcasting, that are utilized by cells to coordinately regulate expression from a large and diverse network of genes. We suspect that this strategy may be employed ubiquitously in cellular signaling and have profound implications on our understandings of eukarytic gene regulation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Career Transition Award (K99)
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Special Emphasis Panel (ZGM1-BRT-9 (KR))
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Remington, Karin A
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California Institute of Technology
Schools of Arts and Sciences
United States
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Sherrard, Kristin M; Fehon, Richard G (2015) The transmembrane protein Crumbs displays complex dynamics during follicular morphogenesis and is regulated competitively by Moesin and aPKC. Development 142:1869-78
Neisch, Amanda L; Formstecher, Etienne; Fehon, Richard G (2013) Conundrum, an ARHGAP18 orthologue, regulates RhoA and proliferation through interactions with Moesin. Mol Biol Cell 24:1420-33
Neisch, Amanda L; Speck, Olga; Stronach, Beth et al. (2010) Rho1 regulates apoptosis via activation of the JNK signaling pathway at the plasma membrane. J Cell Biol 189:311-23