| 1. |
- Krantz, Marcus, 1975, et al.
(författare)
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Robustness and fragility in the high osmolarity glycerol (HOG) pathway in S. cerevisiae
- 2009
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Ingår i: 10th International Conference on Systems Biology (ICSB2009) proceedings, 10th International Conference on Systems Biology (ICSB2009), Aug 30 - Sep 4, Stanford, California, USA.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Cellular signalling networks integrate environmental stimuli with information on cellular status. These networks must be robust against stochastic fluctuations in external stimuli as well as in the amounts of signalling components. Here [1], we challenge the yeast HOG signal transduction pathway with systematic perturbations in components’ expression levels implemented by a “genetic tug-of-war” methodology under various external conditions in search of nodes of fragilities. We observe a substantially higher frequency of fragile nodes in this signal transduction pathway than has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology, with the most sensitive nodes being the proteins PBS2 and SSK1. They are also largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. We studied the influence of seven regulatory motifs around these HOG pathway components in silico through ODE models. Based on the SLN1 and the MAPK modules of a mathematical model of osmoregulation in budding yeast by Klipp et al. [2] we included new motifs and fitted the affected parameters to time courses of dually phosphorylated Hog1p generated by the original model under stress and stress-free conditions. The regulations taken into account by our analysis include Pbs2p scaffolding, Ssk1p and Pbs2p autoactivation, and the formation of a stable dimer between Ssk2p and Ssk1p. A subsequent sensitivity analysis identified Pbs2's role as a scaffold protein and Ssk1p-Ssk2p dimerization as the important contributors to the observed robustness pattern in silico. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.
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| 2. |
- Krantz, Marcus, 1975, et al.
(författare)
-
Robustness and fragility in the yeast high osmolarity glycerol (HOG) signal-transduction pathway.
- 2009
-
Ingår i: Molecular systems biology. - : EMBO. - 1744-4292. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Cellular signalling networks integrate environmental stimuli with the information on cellular status. These networks must be robust against stochastic fluctuations in stimuli as well as in the amounts of signalling components. Here, we challenge the yeast HOG signal-transduction pathway with systematic perturbations in components' expression levels under various external conditions in search for nodes of fragility. We observe a substantially higher frequency of fragile nodes in this signal-transduction pathway than that has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology and they are largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. In silico analysis highlights the impact of model structure on in silico robustness, and suggests complex formation and scaffolding as important contributors to the observed fragility patterns. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.
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| 3. |
- Krantz, Marcus, 1975, et al.
(författare)
-
Robustness and fragility in the yeast High Osmolarity signal transduction pathway
- 2008
-
Ingår i: 2008 Yeast Genetics and Molecular Biology Meeting Program and Abstract Book, 2008 Yeast Genetics and Molecular Biology Meeting, July 22-27, 2008.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The cellular signalling networks that integrate various environmental stimuli with information on cellular status must be robust to stimuli fluctuations as well as to stochastic differences in the amounts of signalling components. Here, we challenge the Hog signal transduction pathway with systematic disturbances in components’ expression levels implemented by a “genetic tug-of-war”, or gToW, methodology. The disturbances were performed under various external perturbations, including pathway activation by osmotic shock. Ideally, the obtained sensitivity profiles will allow us to impose parameter constraints. However, a more important aspect is the qualitative improvement of model structures, when local fragilities cannot be explained by the model structure. The resulting phenotypes in this particular study reflect a wide range of sensitivities, and disperse without any clear pattern over biochemical functions and pathway modules alike, with the most sensitive nodes being PBS2 and SSK1. Surprisingly, the “neighbouring” nodes HOG1 and SSK2 were affected to a much lesser extent, questioning our current understanding.
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| 4. |
- Krantz, Marcus, 1975, et al.
(författare)
-
Robustness and fragility in the yeast High Osmolarity signal transduction pathway
- 2008
-
Ingår i: 9th International Conference on Systems Biology (ICSB2008) proceedings, 9th International Conference on Systems Biology (ICSB2008), August 22-28, Gothenburg.
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Objective: The cellular signalling networks that integrate various environmental stimuli with information on cellular status must be robust to stimuli fluctuations as well as to stochastic differences in the amounts of signalling components. Here, we challenge the high osmolarity glycerol response (HOG) signal transduction pathway in the yeast Saccharomyces cerevisiae with systematic disturbances in components’ expression levels implemented by a “genetic tug-of-war”, or gTOW, methodology. Results: The disturbances were performed under various external perturbations, including pathway activation by osmotic shock. The resulting phenotypes in this particular study reflect a wide range of sensitivities, and disperse without any clear pattern over biochemical functions and pathway modules alike, with the most sensitive nodes being PBS2 and SSK1. Conclusions: Ideally, the obtained sensitivity profiles will allow us to impose parameter constraints. However, a more important aspect is the qualitative improvement of model structures, when local fragilities cannot be explained by the model structure. Surprisingly, the “neighboring” nodes HOG1 and SSK2 were affected to a much lesser extent, questioning our current understanding.
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| 5. |
- Ottosson, Lars-Göran, et al.
(författare)
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Robustness and fragility in the yeast High Osmolarity Glycerol (HOG) signal transduction pathway
- 2009
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Ingår i: Abstracts of the 24th International Conference on Yeast Genetics and Molecular Biology (Supplement to Yeast Volume 26 Issue S1), 25th International Conference on Yeast Genetics & Molecular Biology, July 19-24, Manchester, UK. ; 26:Issue S1
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Konferensbidrag (refereegranskat)abstract
- Cellular signalling networks integrate environmental stimuli with information on cellular status. These networks must be robust against stochastic fluctuations in stimuli as well as in the amounts of signalling components. Here, we challenge the yeast HOG signal transduction pathway with systematic perturbations in components’ expression levels implemented by a “genetic tug-of-war” methodology under various external conditions in search of nodes of fragilities. We observe a substantially higher frequency of fragile nodes in this signal transduction pathway than has been observed for other cellular processes. These fragilities disperse without any clear pattern over biochemical functions or location in pathway topology, with the most sensitive node being the scaffold protein PBS2. They are also largely independent of pathway activation by external stimuli. However, the strongest toxicities are caused by pathway hyperactivation. In silico analysis highlights the impact of model structure on in silico robustness, and suggests complex formation and scaffolding as important contributors to the observed fragility patterns. Thus, in vivo robustness data can be used to discriminate and improve mathematical models.
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