Limits...
Operating regimes of signaling cycles: statics, dynamics, and noise filtering.

Gomez-Uribe C, Verghese GC, Mirny LA - PLoS Comput. Biol. (2007)

Bottom Line: These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions.Numerical simulations show that our analytical results hold well even for noise of large amplitude.We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

ABSTRACT
A ubiquitous building block of signaling pathways is a cycle of covalent modification (e.g., phosphorylation and dephosphorylation in MAPK cascades). Our paper explores the kind of information processing and filtering that can be accomplished by this simple biochemical circuit. Signaling cycles are particularly known for exhibiting a highly sigmoidal (ultrasensitive) input-output characteristic in a certain steady-state regime. Here, we systematically study the cycle's steady-state behavior and its response to time-varying stimuli. We demonstrate that the cycle can actually operate in four different regimes, each with its specific input-output characteristics. These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions. We invoke experimental data that suggest the possibility of signaling cycles operating in one of the new regimes. We then consider the cycle's dynamic behavior, which has so far been relatively neglected. We demonstrate that the intrinsic architecture of the cycles makes them act--in all four regimes--as tunable low-pass filters, filtering out high-frequency fluctuations or noise in signals and environmental cues. Moreover, the cutoff frequency can be adjusted by the cell. Numerical simulations show that our analytical results hold well even for noise of large amplitude. We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways.

Show MeSH

Related in: MedlinePlus

Diagram of the Signaling CycleThe cycle consists of a protein that can be in an inactive (I) or active (A) form. It is activated and deactivated by two enzymatic species, termed kinase (E1) and phosphatase (E2), respectively. The reactions and reaction rates that describe the cycle are shown on the right.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2230677&req=5

pcbi-0030246-g001: Diagram of the Signaling CycleThe cycle consists of a protein that can be in an inactive (I) or active (A) form. It is activated and deactivated by two enzymatic species, termed kinase (E1) and phosphatase (E2), respectively. The reactions and reaction rates that describe the cycle are shown on the right.

Mentions: Each cycle consists of a substrate protein that can be in one of two states: active (e.g., phosphorylated) or inactive (e.g., dephosphorylated), see Figure 1. The protein is activated by a protein kinase that catalyzes a phosphorylation reaction. The protein gets inactivated by a second enzymatic reaction catalyzed by a phosphatase. The activity/concentration of the kinase can be considered as an input of the cycle. The response of the cycle is the level of phosphorylated substrate protein that is not bound to the phosphatase and can thus interact with any downstream components of the signaling pathway.


Operating regimes of signaling cycles: statics, dynamics, and noise filtering.

Gomez-Uribe C, Verghese GC, Mirny LA - PLoS Comput. Biol. (2007)

Diagram of the Signaling CycleThe cycle consists of a protein that can be in an inactive (I) or active (A) form. It is activated and deactivated by two enzymatic species, termed kinase (E1) and phosphatase (E2), respectively. The reactions and reaction rates that describe the cycle are shown on the right.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2230677&req=5

pcbi-0030246-g001: Diagram of the Signaling CycleThe cycle consists of a protein that can be in an inactive (I) or active (A) form. It is activated and deactivated by two enzymatic species, termed kinase (E1) and phosphatase (E2), respectively. The reactions and reaction rates that describe the cycle are shown on the right.
Mentions: Each cycle consists of a substrate protein that can be in one of two states: active (e.g., phosphorylated) or inactive (e.g., dephosphorylated), see Figure 1. The protein is activated by a protein kinase that catalyzes a phosphorylation reaction. The protein gets inactivated by a second enzymatic reaction catalyzed by a phosphatase. The activity/concentration of the kinase can be considered as an input of the cycle. The response of the cycle is the level of phosphorylated substrate protein that is not bound to the phosphatase and can thus interact with any downstream components of the signaling pathway.

Bottom Line: These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions.Numerical simulations show that our analytical results hold well even for noise of large amplitude.We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways.

View Article: PubMed Central - PubMed

Affiliation: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.

ABSTRACT
A ubiquitous building block of signaling pathways is a cycle of covalent modification (e.g., phosphorylation and dephosphorylation in MAPK cascades). Our paper explores the kind of information processing and filtering that can be accomplished by this simple biochemical circuit. Signaling cycles are particularly known for exhibiting a highly sigmoidal (ultrasensitive) input-output characteristic in a certain steady-state regime. Here, we systematically study the cycle's steady-state behavior and its response to time-varying stimuli. We demonstrate that the cycle can actually operate in four different regimes, each with its specific input-output characteristics. These results are obtained using the total quasi-steady-state approximation, which is more generally valid than the typically used Michaelis-Menten approximation for enzymatic reactions. We invoke experimental data that suggest the possibility of signaling cycles operating in one of the new regimes. We then consider the cycle's dynamic behavior, which has so far been relatively neglected. We demonstrate that the intrinsic architecture of the cycles makes them act--in all four regimes--as tunable low-pass filters, filtering out high-frequency fluctuations or noise in signals and environmental cues. Moreover, the cutoff frequency can be adjusted by the cell. Numerical simulations show that our analytical results hold well even for noise of large amplitude. We suggest that noise filtering and tunability make signaling cycles versatile components of more elaborate cell-signaling pathways.

Show MeSH
Related in: MedlinePlus