Time-dependent sensitivity analysis of biological networks: coupled MAPK and PI3K signal transduction pathways

The Journal of Physical Chemistry. a
Dawei Hu, Jian-Min Yuan

Abstract

Sensitivity analysis has been widely used in the studies of complicated chemical reaction and biological networks, for example, in combustion studies and metabolic control analysis of pathways. In the latter cases, the responses of system properties at steady states with respect to changes of parameters, such as initial concentrations and rate constants, are often expressed as sensitivities. Besides steady-state sensitivities, time-dependent sensitivities should be useful; however, the explicit use of them in analyzing complicated biological systems has so far been limited. Using the coupled mitogen activated protein kinase (MAPK)-phophatidylinoisitol 3'-kinase (PI3K) system of the Ras pathways, known to be involved in about 30% of human cancers, as an example, we show that time-dependent sensitivities are useful for the studies of complex biological systems. They provide, for example, the following information: (a) multiple time scales existing in a complex system involving cross-talks and feedback loops; (b) the signs and strengths of responses to perturbations (as system complication increases, the signs of global responses are not always easily determined; for example, response may change sign more than once as time evolves...Continue Reading

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