Bistable switching and excitable behaviour in the activation of Src at mitosis
Hendrik Fuss, Werner Dubitzky, Stephen Downes, Mary Jo Kurth
Motivation: The protein tyrosine kinase Src is involved in a multitude of biochemical pathways and cellular functions. A complex network of interactions with other kinases and phosphatases obscures its precise mode of operation. Results: We have constructed a semi-quantitative computational dynamic systems model of the activation of Src at mitosis based on protein interactions described in the literature. Through numerical simulation and bifurcation analysis we show that Src regulation involves a bistable switch, a pattern increasingly recognised as essential to biochemical signalling. The switch is operated by the tyrosine kinase CSK, which itself is involved in a negative feedback loop with Src. Negative feedback generates an excitable system, which produces transient activation of Src. One of the system parameters, which is linked to the cyclin dependent kinase cdc2, controls excitability via a second bistable switch. This topology allows for differentiated responses to a multitude of signals. The model offers explanations for the existence of the positive and negative feedback loops involving protein tyrosine phosphatase alpha (PTPa) and translocation of CSK and predicts a specific relationship between Src phosphorylation and activity.
E158-E165
https://doi.org/10.1093/bioinformatics/btl201
10.1093/bioinformatics/btl201
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Negative Feedback Mathematics
Activation Mathematics
Switch Mathematics
Mitosis Medicine & Life Sciences
Chemical activation Engineering & Materials Science
Feedback Loop Mathematics
Phosphatases Engineering & Materials Science
Protein Mathematics
Fuss, H., Dubitzky, W., Downes, S., & Kurth, M. J. (2006). Bistable switching and excitable behaviour in the activation of Src at mitosis. Bioinformatics, 22(14), E158-E165. https://doi.org/10.1093/bioinformatics/btl201
Fuss, Hendrik ; Dubitzky, Werner ; Downes, Stephen ; Kurth, Mary Jo. / Bistable switching and excitable behaviour in the activation of Src at mitosis. In: Bioinformatics. 2006 ; Vol. 22, No. 14. pp. E158-E165.
@article{2cdc7f4e95e3457d90d45a422f781049,
title = "Bistable switching and excitable behaviour in the activation of Src at mitosis",
abstract = "Motivation: The protein tyrosine kinase Src is involved in a multitude of biochemical pathways and cellular functions. A complex network of interactions with other kinases and phosphatases obscures its precise mode of operation. Results: We have constructed a semi-quantitative computational dynamic systems model of the activation of Src at mitosis based on protein interactions described in the literature. Through numerical simulation and bifurcation analysis we show that Src regulation involves a bistable switch, a pattern increasingly recognised as essential to biochemical signalling. The switch is operated by the tyrosine kinase CSK, which itself is involved in a negative feedback loop with Src. Negative feedback generates an excitable system, which produces transient activation of Src. One of the system parameters, which is linked to the cyclin dependent kinase cdc2, controls excitability via a second bistable switch. This topology allows for differentiated responses to a multitude of signals. The model offers explanations for the existence of the positive and negative feedback loops involving protein tyrosine phosphatase alpha (PTPa) and translocation of CSK and predicts a specific relationship between Src phosphorylation and activity.",
author = "Hendrik Fuss and Werner Dubitzky and Stephen Downes and Kurth, {Mary Jo}",
note = "14th Conference on Intelligent Systems for Molecular Biology, Fortaleza, BRAZIL, AUG 06-10, 2006",
doi = "10.1093/bioinformatics/btl201",
pages = "E158--E165",
journal = "Bioinformatics",
Fuss, H, Dubitzky, W, Downes, S & Kurth, MJ 2006, 'Bistable switching and excitable behaviour in the activation of Src at mitosis', Bioinformatics, vol. 22, no. 14, pp. E158-E165. https://doi.org/10.1093/bioinformatics/btl201
Bistable switching and excitable behaviour in the activation of Src at mitosis. / Fuss, Hendrik; Dubitzky, Werner; Downes, Stephen; Kurth, Mary Jo.
In: Bioinformatics, Vol. 22, No. 14, 07.2006, p. E158-E165.
T1 - Bistable switching and excitable behaviour in the activation of Src at mitosis
AU - Fuss, Hendrik
AU - Dubitzky, Werner
AU - Downes, Stephen
AU - Kurth, Mary Jo
N1 - 14th Conference on Intelligent Systems for Molecular Biology, Fortaleza, BRAZIL, AUG 06-10, 2006
N2 - Motivation: The protein tyrosine kinase Src is involved in a multitude of biochemical pathways and cellular functions. A complex network of interactions with other kinases and phosphatases obscures its precise mode of operation. Results: We have constructed a semi-quantitative computational dynamic systems model of the activation of Src at mitosis based on protein interactions described in the literature. Through numerical simulation and bifurcation analysis we show that Src regulation involves a bistable switch, a pattern increasingly recognised as essential to biochemical signalling. The switch is operated by the tyrosine kinase CSK, which itself is involved in a negative feedback loop with Src. Negative feedback generates an excitable system, which produces transient activation of Src. One of the system parameters, which is linked to the cyclin dependent kinase cdc2, controls excitability via a second bistable switch. This topology allows for differentiated responses to a multitude of signals. The model offers explanations for the existence of the positive and negative feedback loops involving protein tyrosine phosphatase alpha (PTPa) and translocation of CSK and predicts a specific relationship between Src phosphorylation and activity.
AB - Motivation: The protein tyrosine kinase Src is involved in a multitude of biochemical pathways and cellular functions. A complex network of interactions with other kinases and phosphatases obscures its precise mode of operation. Results: We have constructed a semi-quantitative computational dynamic systems model of the activation of Src at mitosis based on protein interactions described in the literature. Through numerical simulation and bifurcation analysis we show that Src regulation involves a bistable switch, a pattern increasingly recognised as essential to biochemical signalling. The switch is operated by the tyrosine kinase CSK, which itself is involved in a negative feedback loop with Src. Negative feedback generates an excitable system, which produces transient activation of Src. One of the system parameters, which is linked to the cyclin dependent kinase cdc2, controls excitability via a second bistable switch. This topology allows for differentiated responses to a multitude of signals. The model offers explanations for the existence of the positive and negative feedback loops involving protein tyrosine phosphatase alpha (PTPa) and translocation of CSK and predicts a specific relationship between Src phosphorylation and activity.
U2 - 10.1093/bioinformatics/btl201
DO - 10.1093/bioinformatics/btl201
SP - E158-E165
JO - Bioinformatics
JF - Bioinformatics
Fuss H, Dubitzky W, Downes S, Kurth MJ. Bistable switching and excitable behaviour in the activation of Src at mitosis. Bioinformatics. 2006 Jul;22(14):E158-E165. https://doi.org/10.1093/bioinformatics/btl201