In many biological signal transduction pathways, multiple input signals converge on a shared set of signaling components, which route each input to the appropriate output. How is signaling specificity maintained so that am signal does not corrupt the response of another? For example in yeast, the signals for mating, invasive growth, and osmotic stress are all funneled through the same MAPK (Mitogen Activating Protein Kinase) cascade although each elicits a different response. Here we propose to investigate the dynamics and regulation of signaling cascades through an integrated program of mathematical and experimental approaches. We will develop state-of-the-art mathematical theory and computational tools to analyze and simulate signal transduction pathways, with an emphasis on scaffolding, spatial dynamics, specificity, and how they relate to one another. Our ultimate goal is to develop a theoretical framework for understanding how proper signal processing occurs in highly interconnected biochemical networks and to validate them by detailed modeling and experimentation focusing on the yeast MAPK system. As steps toward this goal, we will first develop generic representations of signaling pathways with shared components and test them in the yeast MAPK system. In this setting, we will rigorously address how scaffolds and feedback regulation can give rise to specificity and what are the limits and tradeoffs. Then, we will include spatial dynamics and explore the implementation of specificity-promoting mechanisms. A hierarchy of models from microscopic levels involving spatial interplay between the scaffold and the resident kinases to a full-scale network level for the yeast MAPK system will be explored. We plan to test our conclusions and predictions from such mathematical and computational analysis by performing selected experiments. The quantitative analysis will involve control theory and large systems of nonlinear ordinary and partial differential equations on networks. New mathematical theories and numerical algorithms will have to be developed for the analysis and simulations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM075309-04
Application #
7404394
Study Section
Special Emphasis Panel (ZGM1-CBCB-0 (BM))
Program Officer
Lyster, Peter
Project Start
2005-04-01
Project End
2011-03-31
Budget Start
2008-04-01
Budget End
2011-03-31
Support Year
4
Fiscal Year
2008
Total Cost
$266,787
Indirect Cost
Name
University of California Irvine
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Chou, Ching-Shan; Moore, Travis I; Nie, Qing et al. (2015) Alternative cell polarity behaviours arise from changes in G-protein spatial dynamics. IET Syst Biol 9:52-63
Moore, Travis I; Tanaka, Hiromasa; Kim, Hyung Joon et al. (2013) Yeast G-proteins mediate directional sensing and polarization behaviors in response to changes in pheromone gradient direction. Mol Biol Cell 24:521-34
Chan, Carlo; Liu, Xinfeng; Wang, Liming et al. (2012) Protein scaffolds can enhance the bistability of multisite phosphorylation systems. PLoS Comput Biol 8:e1002551
Zhao, Su; Ovadia, Jeremy; Liu, Xinfeng et al. (2011) Operator Splitting Implicit Integration Factor Methods for Stiff Reaction-Diffusion-Advection Systems. J Comput Phys 230:5996-6009
Lei, Jinzhi; Wan, Frederic Y M; Lander, Arthur D et al. (2011) ROBUSTNESS OF SIGNALING GRADIENT IN DROSOPHILA WING IMAGINAL DISC. Discrete Continuous Dyn Syst Ser B 16:835-866
Chou, Ching-Shan; Bardwell, Lee; Nie, Qing et al. (2011) Noise filtering tradeoffs in spatial gradient sensing and cell polarization response. BMC Syst Biol 5:196
Zheng, Zhenzhen; Chou, Ching-Shan; Yi, Tau-Mu et al. (2011) Mathematical analysis of steady-state solutions in compartment and continuum models of cell polarization. Math Biosci Eng 8:1135-68
Liu, Xinfeng; Bardwell, Lee; Nie, Qing (2010) A combination of multisite phosphorylation and substrate sequestration produces switchlike responses. Biophys J 98:1396-407
Christley, Scott; Lee, Briana; Dai, Xing et al. (2010) Integrative multicellular biological modeling: a case study of 3D epidermal development using GPU algorithms. BMC Syst Biol 4:107
Wang, Liming; Xin, Jack; Nie, Qing (2010) A critical quantity for noise attenuation in feedback systems. PLoS Comput Biol 6:e1000764

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