(573c) Sensitivity Analysis-Based Approach for Identifying Key Steps in Cell Signaling for Hepatocytes Stimulated by Il-6

Understanding the regulatory mechanism of cell signaling can help in designing therapies for many diseases and injuries. However, the large number of components involved in the cell signaling pathways and the interaction between different signaling pathways (cross-talk) return results that are difficult to interpret. To address this issue for some specific applications a number of mathematical models have been developed to improve the understanding of regulatory mechanism in the signaling pathways [1, 2, 3, 4]. Sensitivity analysis forms a core component for improving the understanding of the signaling networks as it can be used to identify the contribution of individual parts of the model to the signaling pathway.

In this work, direct differential method (DDM) [5] has been applied to identify the key steps in the mathematical model developed by Singh et al. [6], which describes signal transduction in hepatocytes induced by interleukin-6 (IL-6). This model contains two pathways: Janus-associated kinases (JAK) & signal transducers and transcription factors (STAT 3) are activated in one pathway while the other pathway involves the activation of mitogen-activated protein kinases (MAPK). Sensitivity analysis has been applied to determine the effect of interactions between the two pathways on the system output. Further, the influence of other regulatory mechanism and perturbation in the kinetic parameters on the system output has been analyzed.

The analysis shows that the nuclear STAT3 dimer, considered as an output of the signal transduction induced by IL-6, is most sensitive to dephosphorylation by a nuclear phoshphatase, PP2. The phosphorylated nuclear STAT3 dimer diffuses into the nucleus, undergoes dephosphorylation and is exported back to the cytosol to participate in further signal transduction. However, in the absence of PP2, STAT3 accumulates in the nucleus, resulting in low STAT3 concentration in the cytosol. Ultimately, this effect inhibits cell signaling through the JAK/STAT pathway. The phosphorylation of STAT3 in the cytosol, phosphorylation of IL-6 receptor complex and negative feedback regulation by SOCS3 (suppressor of cytokine signaling 3) protein, respectively, are other important events for signal transduction that have been identified by this investigation.

In addition, the effect of perturbations of the kinetic parameters on the system output has been analyzed by Fourier amplitude sensitivity test (FAST) method [5]. Unlike the DDM, in FAST method the parameters are varied simultaneously. However, like DDM, the FAST method identifies that the output is most sensitive to nuclear STAT3 dephosphorylation by a nuclear phoshphatase.

References:

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[2] Yamada S, Shiono S, Joo A, Yoshimura A. 2003. Control mechanism of JAK/STAT signal transduction pathway. FEBS Letters 534: 190-196.

[3] Asthagiri A.R., Lauffenburger D.A. 2001. A computational study of feedback effects on signal dynamics in a mitogen activated protein kinase (MAPK) pathway model. Biotechnology Prog. 17, 227-239.

[4] Bhalla U.S., Iyengar R. 2001. Emergent properties of networks of biological signaling pathways. Science 283, 381-387.

[5] Varma A., Morbidelli M., Wu H. 1999. Parametric Senstivity in Chemical Systems. Cambridge University Press, New York.

[6] Singh A. K., Jayaraman A., Hahn J. 2005. Mathematical model of IL-6 signal transduction in hepatocytes. Proceedings FOSBE, UCSB, Santa Barbara, CA.