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Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control.

Mahdavi A, Davey RE, Bhola P, Yin T, Zandstra PW - PLoS Comput. Biol. (2007)

Bottom Line: Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation.Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking.This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3) pathway kinetics, a signaling network involved in embryonic stem cell (ESC) self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

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Global Sensitivity Analysis Based on Stat3 Activation(A) Individual rate constants were changed 5-fold, and a Euclidean distance measurement was used to determine the resultant change in the Stat3 activation profile. Normalized Euclidean distance measurements are plotted to show the sensitivity of Stat3 activation to each parameter.(B) Global sensitivity analysis results show changes in Stat3 activation (measured by Euclidean distance) due to 5-fold changes in combinations of parameters pairs, shown along the x- and y-axis. The sensitivity is represented using color code, with corresponding Euclidean distance values shown in the color bar. Hierarchical clustering (indicated on the left) is based on correlations between rows of rate constants to demonstrate groups of parameters which interact similarly. Clustering was perfomed using Matlab software by Mathworks. Rate constants, which are grouped together, are color-coded using circular dots, and the color code is included in Figure 1. Sensitivity analysis predictions for the Stat3 nuclear export parameter (marked by square), and receptor phosphorylation (marked by triangle), and their interaction (marked by circle) are shown in (C). Sensitivity trends which were predicted in (C) are experimentally verified (D), demonstrating that predicted trends are relevant.(E) Sensitivity analysis trends of interaction of SOCS3 transcription and receptor production (marked by hexagon) and SOCS3 translation and receptor production (marked by cross) are in agreement with experimental results shown in (F).
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pcbi-0030130-g005: Global Sensitivity Analysis Based on Stat3 Activation(A) Individual rate constants were changed 5-fold, and a Euclidean distance measurement was used to determine the resultant change in the Stat3 activation profile. Normalized Euclidean distance measurements are plotted to show the sensitivity of Stat3 activation to each parameter.(B) Global sensitivity analysis results show changes in Stat3 activation (measured by Euclidean distance) due to 5-fold changes in combinations of parameters pairs, shown along the x- and y-axis. The sensitivity is represented using color code, with corresponding Euclidean distance values shown in the color bar. Hierarchical clustering (indicated on the left) is based on correlations between rows of rate constants to demonstrate groups of parameters which interact similarly. Clustering was perfomed using Matlab software by Mathworks. Rate constants, which are grouped together, are color-coded using circular dots, and the color code is included in Figure 1. Sensitivity analysis predictions for the Stat3 nuclear export parameter (marked by square), and receptor phosphorylation (marked by triangle), and their interaction (marked by circle) are shown in (C). Sensitivity trends which were predicted in (C) are experimentally verified (D), demonstrating that predicted trends are relevant.(E) Sensitivity analysis trends of interaction of SOCS3 transcription and receptor production (marked by hexagon) and SOCS3 translation and receptor production (marked by cross) are in agreement with experimental results shown in (F).

Mentions: Closed arrows indicate biochemical reactions, open arrows show transport such as transport into nuclear compartment, and double arrows indicate reversibility. All surface receptors and complexes are internalized similarly, internalized complexes are degraded, and new receptors are constitutively produced. Color-coded dots next to kinetic parameters correspond to grouping of parameters from Figure 5 as explained in text.


Sensitivity analysis of intracellular signaling pathway kinetics predicts targets for stem cell fate control.

Mahdavi A, Davey RE, Bhola P, Yin T, Zandstra PW - PLoS Comput. Biol. (2007)

Global Sensitivity Analysis Based on Stat3 Activation(A) Individual rate constants were changed 5-fold, and a Euclidean distance measurement was used to determine the resultant change in the Stat3 activation profile. Normalized Euclidean distance measurements are plotted to show the sensitivity of Stat3 activation to each parameter.(B) Global sensitivity analysis results show changes in Stat3 activation (measured by Euclidean distance) due to 5-fold changes in combinations of parameters pairs, shown along the x- and y-axis. The sensitivity is represented using color code, with corresponding Euclidean distance values shown in the color bar. Hierarchical clustering (indicated on the left) is based on correlations between rows of rate constants to demonstrate groups of parameters which interact similarly. Clustering was perfomed using Matlab software by Mathworks. Rate constants, which are grouped together, are color-coded using circular dots, and the color code is included in Figure 1. Sensitivity analysis predictions for the Stat3 nuclear export parameter (marked by square), and receptor phosphorylation (marked by triangle), and their interaction (marked by circle) are shown in (C). Sensitivity trends which were predicted in (C) are experimentally verified (D), demonstrating that predicted trends are relevant.(E) Sensitivity analysis trends of interaction of SOCS3 transcription and receptor production (marked by hexagon) and SOCS3 translation and receptor production (marked by cross) are in agreement with experimental results shown in (F).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1913098&req=5

pcbi-0030130-g005: Global Sensitivity Analysis Based on Stat3 Activation(A) Individual rate constants were changed 5-fold, and a Euclidean distance measurement was used to determine the resultant change in the Stat3 activation profile. Normalized Euclidean distance measurements are plotted to show the sensitivity of Stat3 activation to each parameter.(B) Global sensitivity analysis results show changes in Stat3 activation (measured by Euclidean distance) due to 5-fold changes in combinations of parameters pairs, shown along the x- and y-axis. The sensitivity is represented using color code, with corresponding Euclidean distance values shown in the color bar. Hierarchical clustering (indicated on the left) is based on correlations between rows of rate constants to demonstrate groups of parameters which interact similarly. Clustering was perfomed using Matlab software by Mathworks. Rate constants, which are grouped together, are color-coded using circular dots, and the color code is included in Figure 1. Sensitivity analysis predictions for the Stat3 nuclear export parameter (marked by square), and receptor phosphorylation (marked by triangle), and their interaction (marked by circle) are shown in (C). Sensitivity trends which were predicted in (C) are experimentally verified (D), demonstrating that predicted trends are relevant.(E) Sensitivity analysis trends of interaction of SOCS3 transcription and receptor production (marked by hexagon) and SOCS3 translation and receptor production (marked by cross) are in agreement with experimental results shown in (F).
Mentions: Closed arrows indicate biochemical reactions, open arrows show transport such as transport into nuclear compartment, and double arrows indicate reversibility. All surface receptors and complexes are internalized similarly, internalized complexes are degraded, and new receptors are constitutively produced. Color-coded dots next to kinetic parameters correspond to grouping of parameters from Figure 5 as explained in text.

Bottom Line: Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation.Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking.This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, Ontario, Canada.

ABSTRACT
Directing stem cell fate requires knowledge of how signaling networks integrate temporally and spatially segregated stimuli. We developed and validated a computational model of signal transducer and activator of transcription-3 (Stat3) pathway kinetics, a signaling network involved in embryonic stem cell (ESC) self-renewal. Our analysis identified novel pathway responses; for example, overexpression of the receptor glycoprotein-130 results in reduced pathway activation and increased ESC differentiation. We used a systematic in silico screen to identify novel targets and protein interactions involved in Stat3 activation. Our analysis demonstrates that signaling activation and desensitization (the inability to respond to ligand restimulation) is regulated by balancing the activation state of a distributed set of parameters including nuclear export of Stat3, nuclear phosphatase activity, inhibition by suppressor of cytokine signaling, and receptor trafficking. This knowledge was used to devise a temporally modulated ligand delivery strategy that maximizes signaling activation and leads to enhanced ESC self-renewal.

Show MeSH
Related in: MedlinePlus