Robustness of signal transduction pathways
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Cellular and Molecular Life Sciences
REVIEW
Robustness of signal transduction pathways Nils Blu¨thgen • Stefan Legewie
Received: 4 July 2012 / Revised: 5 September 2012 / Accepted: 6 September 2012 / Published online: 25 September 2012 Ó Springer Basel AG 2012
Abstract Signal transduction pathways transduce information about the outside of the cell to the nucleus, regulating gene expression and cell fate. To reliably inform the cell about its surroundings, information transfer has to be robust against typical perturbation that a cell experiences. Robustness of several mammalian signaling pathways has been studied recently by quantitative experimentation and using mathematical modeling. Here, we review these studies, and describe the emerging concepts of robustness and the underlying mechanisms. Keywords Robustness Feedback Signal transduction Adaptation Sensitivity Heterogeneity MAPK BMP
Introduction Systems that remain functional although they experience a perturbation are termed robust [1]. Robustness is a central feature of living systems, as these systems face many strong perturbations on all levels [2]. Perturbations range from changing environmental conditions in which an N. Blu¨thgen Institute of Pathology, Charite´ Universita¨tsmedizin Berlin, Charite´platz 1, 10117 Berlin, Germany N. Blu¨thgen (&) Institute for Theoretical Biology, Humboldt University Berlin, Invalidenstraße 43, 10115 Berlin, Germany e-mail: [email protected] S. Legewie Institute of Molecular Biology, Ackermannweg 4, 55128 Mainz, Germany e-mail: [email protected]
organism lives, wounds and infections that act on the tissue level down to perturbation of the cellular state due to fluctuation in supply of nutrients or stochasticity and uncertainty in molecular processes [3]. Robustness is typically limited to moderate perturbation magnitudes, and can only be maintained for certain molecular species and dynamical properties of the network. Quantitative perturbation-response measurements are thus required to pin down precisely which functions a system can maintain. Recently, robustness of signaling pathways has been investigated by several groups. These studies employed theoretical concepts such as parameter optimization and sensitivity analysis to identify robustness-promoting mechanisms, and to derive experimentally testable predictions. Here, we review these findings, discuss how robustness can be investigated, and how it is implemented in signaling pathways.
Types of biological robustness in signaling pathways The function of signaling pathways is to transduce information about the outside of the cell and the cellular state to the nucleus, where they ultimately inform and regulate the expression of genetic material. The mode by which signal transduction pathways transduce information may be very different for different pathways. Some signaling pathways are thought to faithfully report the concentrations of ligands at the outside of the cell to the nucleus, thus transducing quantitative information about the e
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