« Previous AbstractThe importance of chemosensory clues in Aguaruna tree classification and identification    Next Abstract[Action of urine odor on the duration of the estrus cycle in the guinea pig] »

PLoS Comput Biol

Title:		Determinants of cell-to-cell variability in protein kinase signaling
Author(s):		Jeschke M; Baumgartner S; Legewie S;
Address:		"Institute of Molecular Biology (IMB), Mainz, Germany"
Journal Title:		PLoS Comput Biol
Year:		2013
Volume:		20131205
Issue:		12
Page Number:		e1003357 -
DOI:		10.1371/journal.pcbi.1003357
ISSN/ISBN:		1553-7358 (Electronic) 1553-734X (Print) 1553-734X (Linking)
Abstract:		"Cells reliably sense environmental changes despite internal and external fluctuations, but the mechanisms underlying robustness remain unclear. We analyzed how fluctuations in signaling protein concentrations give rise to cell-to-cell variability in protein kinase signaling using analytical theory and numerical simulations. We characterized the dose-response behavior of signaling cascades by calculating the stimulus level at which a pathway responds ('pathway sensitivity') and the maximal activation level upon strong stimulation. Minimal kinase cascades with gradual dose-response behavior show strong variability, because the pathway sensitivity and the maximal activation level cannot be simultaneously invariant. Negative feedback regulation resolves this trade-off and coordinately reduces fluctuations in the pathway sensitivity and maximal activation. Feedbacks acting at different levels in the cascade control different aspects of the dose-response curve, thereby synergistically reducing the variability. We also investigated more complex, ultrasensitive signaling cascades capable of switch-like decision making, and found that these can be inherently robust to protein concentration fluctuations. We describe how the cell-to-cell variability of ultrasensitive signaling systems can be actively regulated, e.g., by altering the expression of phosphatase(s) or by feedback/feedforward loops. Our calculations reveal that slow transcriptional negative feedback loops allow for variability suppression while maintaining switch-like decision making. Taken together, we describe design principles of signaling cascades that promote robustness. Our results may explain why certain signaling cascades like the yeast pheromone pathway show switch-like decision making with little cell-to-cell variability"
Keywords:		"Feedback *Models, Biological Protein Kinases/*metabolism *Signal Transduction;"
Notes:		"MedlineJeschke, Matthias Baumgartner, Stephan Legewie, Stefan eng Research Support, Non-U.S. Gov't 2013/12/18 PLoS Comput Biol. 2013; 9(12):e1003357. doi: 10.1371/journal.pcbi.1003357. Epub 2013 Dec 5"