Results: 5

1.
FIG. 2.

FIG. 2. From: Systemic Redox Regulation of Cellular Information Processing.

Topological features influence the contribution of phosphatases. Simulations were performed by setting different combinations of phosphatases as redox sensitive. (A) ERKpp levels when only a single phosphatase is redox sensitive. The same oxidation and reduction rates were assigned to each phosphatase for consistency. Oxidation of phosphatases with substrates further removed from ERK leads to greater amplification of the response. (B) ERKpp response when pairs of phosphatases are redox sensitive. The output for two phosphatases appears to be a qualitative sum of the outputs when individual phosphatases are redox sensitive. (To see this illustration in color the reader is referred to the Web version of this article at www.liebertonline.com/ars). (Further details regarding Figure 2 may be viewed as Supplementary Data; available online at www.liebertonline.com/ars).

Gaurav Dwivedi, et al. Antioxid Redox Signal. 2012 February 15;16(4):374-380.
2.
FIG. 4.

FIG. 4. From: Systemic Redox Regulation of Cellular Information Processing.

Oxidative inhibition of MAPK. (A) Reversible oxidative inhibition of MAPK was modeled by modifying the model in Figure 1. The dual-phosphorylated form of MAPK was assumed to be redox sensitive, and the oxidation was reversible. (B) Taking the MAPK cascade as corresponding to the p38 signaling pathway, simulations were performed with dually phosphorylated p38 being sensitive or not to oxidation. Reduced, dually phosphorylated p38 unbound to other proteins was assumed to be the enzymatically active form, and the oxidized form was catalytically inactive. Inclusion of reversible oxidation resulted in low p38 activity sustained over a longer period of time. (To see this illustration in color the reader is referred to the Web version of this article at www.liebertonline.com/ars). (Further details regarding Figure 4 may be viewed as Supplementary Data; available online at www.liebertonline.com/ars). MAPK, mitogen-activated protein kinase.

Gaurav Dwivedi, et al. Antioxid Redox Signal. 2012 February 15;16(4):374-380.
3.
FIG. 3.

FIG. 3. From: Systemic Redox Regulation of Cellular Information Processing.

Compartmentalization of redox potential affects signaling. (A) The model optimized to HLE B3 cell data (Fig. 1) was modified to include nucleo-cytoplasmic shuttling of ERK and its phosphatase P3. Nuclear entry and exit were modeled as first order reactions with equal rate constants and were assumed to be the same for all proteins concerned. (B) The nucleus was assumed to be at an identical oxidative state as the cytosol. Cytosolic and nuclear levels of ERK were predicted to be similar. (C) The nucleus was modeled as a more reduced compartment so that there was no protein oxidation in the nucleus. Protein reduction rates were taken to be the same in both compartments. Both the nuclear and cytosolic signals are attenuated compared to panel (B). (To see this illustration in color the reader is referred to the Web version of this article at www.liebertonline.com/ars). (Further details regarding Figure 3 may be viewed as Supplementary Data; available online at www.liebertonline.com/ars).

Gaurav Dwivedi, et al. Antioxid Redox Signal. 2012 February 15;16(4):374-380.
4.
FIG. 5.

FIG. 5. From: Systemic Redox Regulation of Cellular Information Processing.

Increased complexity leads to varied ROS regulation. (A) The Akt-ERK crosstalk model was adopted from (3) and modified to include oxidative inhibition of phosphatases MKP3 and PP2A. ROS production was assumed to be a Nox dependent process requiring the presence of active PI3K and RasGTP for Nox activation. ROS production was, therefore, modeled as a process driven by active PI3K and RasGTP, and the decay was a first-order process. (B) Redox-sensitive phosphatases result in amplification of ERKpp compared with a condition where no protein is redox sensitive. (C) By strengthening the inhibitory effect of Akt on Raf while at the same time weakening the control of PP2A on MEK dephosphorylation (altering three parameters in all), the qualitative effect of ROS on ERKpp was reversed as compared with panel (B). With the altered parameters, the oxidation-sensitive model resulted in signal attenuation compared with the redox-insensitive model. (To see this illustration in color the reader is referred to the Web version of this article at www.liebertonline.com/ars). (Further details regarding Figure 5 may be viewed as Supplementary Data; available online at www.liebertonline.com/ars).

Gaurav Dwivedi, et al. Antioxid Redox Signal. 2012 February 15;16(4):374-380.
5.
FIG. 1.

FIG. 1. From: Systemic Redox Regulation of Cellular Information Processing.

Computational model of redox regulation in lens epithelial (HLE B3) cells. (A) ERK signaling pathway with two-step phosphorylation was modeled. Phosphatases were reversibly inhibited by oxidation. Species highlighted in blue (RasGTP and ROS) were supplied as input functions to the model. (B) Parameters of the model were optimized to fit experimental measurements of MEK and ERK phosphorylation after PDGF stimulation of HLE B3 cells (1). The ROS input function (inset) was obtained by fitting a curve to measured DCF fluorescence. (C) Catalase pretreatment was simulated using the model fitted in B by setting ROS level to 0. (D) Exogenous bolus addition of H2O2 was simulated using the fitted model in (B) with an exponentially decaying ROS curve (inset), and RasGTP was not allowed to change from its basal level. Optimization of the ROS curve alone was sufficient to fit the experimental data. ERKpp levels fail to increase substantially if phosphatases P1 and P2 are not sensitive to oxidation. (Further details regarding Figure 1 may be viewed as Supplementary Data; available online at www.liebertonline.com/ars). ROS, reactive oxygen species; ERKpp, phosphorylated ERK; PDGF, platelet-derived growth factor.

Gaurav Dwivedi, et al. Antioxid Redox Signal. 2012 February 15;16(4):374-380.

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