An investigation of spatial signal transduction in cellular networks

Alam-Nazki, Aiman; Krishnan, J.

doi:10.1186/1752-0509-6-83

Cited by 11 publications

(6 citation statements)

References 54 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Case 2: Diffusible species in circuit. In the incoherent feedforward motif KR09, it has been shown that having a diffusible species can give rise to adaptation with spatial sensing, and that differences in diffusivity can be used to achieve different combinations of temporal and spatial responses (see [ 8 ] where the model was formulated and also [ 34 – 36 , 53 ]). In the context of the three node motif with inflow and outflow, it can easily be seen that having species A diffuse can give rise to non-adaptive behaviour in static spatial gradients: the essential insight being that the diffusion term contributes an extra “sink" which along with outflow has to match inflow to the system.…”

Section: Resultsmentioning

confidence: 99%

Adaptive information processing of network modules to dynamic and spatial stimuli

Krishnan

Floros

2019

BMC Syst Biol

View full text Add to dashboard Cite

BackgroundAdaptation and homeostasis are basic features of information processing in cells and seen in a broad range of contexts. Much of the current understanding of adaptation in network modules/motifs is based on their response to simple stimuli. Recently, there have also been studies of adaptation in dynamic stimuli. However a broader synthesis of how different circuits of adaptation function, and which circuits enable a broader adaptive behaviour in classes of more complex and spatial stimuli is largely missing.ResultsWe study the response of a variety of adaptive circuits to time-varying stimuli such as ramps, periodic stimuli and static and dynamic spatial stimuli. We find that a variety of responses can be seen in ramp stimuli, making this a basis for discriminating between even similar circuits. We also find that a number of circuits adapt exactly to ramp stimuli, and dissect these circuits to pinpoint what characteristics (architecture, feedback, biochemical aspects, information processing ingredients) allow for this. These circuits include incoherent feedforward motifs, inflow-outflow motifs and transcritical circuits. We find that changes in location in such circuits where a signal acts can result in non-adaptive behaviour in ramps, even though the location was associated with exact adaptation in step stimuli. We also demonstrate that certain augmentations of basic inflow-outflow motifs can alter the behaviour of the circuit from exact adaptation to non-adaptive behaviour. When subject to periodic stimuli, some circuits (inflow-outflow motifs and transcritical circuits) are able to maintain an average output independent of the characteristics of the input. We build on this to examine the response of adaptive circuits to static and dynamic spatial stimuli. We demonstrate how certain circuits can exhibit a graded response in spatial static stimuli with an exact maintenance of the spatial mean-value. Distinct features which emerge from the consideration of dynamic spatial stimuli are also discussed. Finally, we also build on these results to show how different circuits which show any combination of presence or absence of exact adaptation in ramps, exact mainenance of time average output in periodic stimuli and exact maintenance of spatial average of output in static spatial stimuli may be realized.ConclusionsBy studying a range of network circuits/motifs on one hand and a range of stimuli on the other, we isolate characteristics of these circuits (structural) which enable different degrees of exact adaptive and homeostatic behaviour in such stimuli, how they may be combined, and also identify cases associated with non-homeostatic behaviour. We also reveal constraints associated with locations where signals may act to enable homeostatic behaviour and constraints associated with augmentations of circuits. This consideration of multiple experimentally/naturally relevant stimuli along with circuits of adaptation of relevance in natural and engineered biology, provides a platform for deepening our understandin...

show abstract

Section: Resultsmentioning

confidence: 99%

Adaptive information processing of network modules to dynamic and spatial stimuli

Krishnan

Floros

2019

BMC Syst Biol

View full text Add to dashboard Cite

show abstract

“…To gain insights into these questions, we will focus on the spatial dimension to signal transduction in a basic building block of posttranslational modification: a covalent modification cycle (8). We do this because this is a ubiquitously occurring unit in cell signaling, and understanding these issues here serves as a platform for understanding similar issues in more complex networks, complementing our previous study (9). We will systematically examine spatial aspects of signal transduction in this module by considering in turn the effects of graded signals, diffusion of individual entities, and localization of individual species, and the combination of these factors.…”

Section: Introductionmentioning

confidence: 93%

Covalent Modification Cycles through the Spatial Prism

Alam-Nazki

Krishnan

2013

Biophysical Journal

Self Cite

View full text Add to dashboard Cite

Covalent modification cycles are basic units and building blocks of posttranslational modification and cellular signal transduction. We systematically explore different spatial aspects of signal transduction in covalent modification cycles by starting with a basic temporal cycle as a reference and focusing on steady-state signal transduction. We consider, in turn, the effect of diffusion on spatial signal transduction, spatial analogs of ultrasensitive behavior, and the interplay between enzyme localization and substrate diffusion. Our analysis reveals the need to explicitly account for kinetics and diffusional transport (and localization) of enzymes, substrates, and complexes. It demonstrates a complex and subtle interplay between spatial heterogeneity, diffusion, and localization. Overall, examining the spatial dimension of covalent modification reveals that 1), there are important differences between spatial and temporal signal transduction even in this cycle; and 2), spatial aspects may play a substantial role in affecting and distorting information transfer in modules/networks that are usually studied in purely temporal terms. This has important implications for the systematic understanding of signaling in covalent modification cycles, pathways, and networks in multiple cellular contexts.

show abstract

“…Model-based studies indicate that positive feedback loop motifs with mutually activating genes, protein covalent modification cycles with autocatalysis, and enzymatic cascades produce transcritical bifurcations ( Aguda 1999 ; Alam-Nazki and Krishnan 2012 ; Widder et al 2007 ). Positive and negative feedback regulation formed between transcription factor E2F and inhibitor protein RB may underlie a transcritical bifurcation for the restriction point transition from G 0 to G 1 in the cell cycle stimulated by mitogens ( Swat et al 2004 ).…”

Section: Bifurcation Network Motifsmentioning

confidence: 99%

Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses

Zhang

Bhattacharya

Conolly

et al. 2014

Environ Health Perspect

View full text Add to dashboard Cite

Background: Increasingly, there is a move toward using in vitro toxicity testing to assess human health risk due to chemical exposure. As with in vivo toxicity testing, an important question for in vitro results is whether there are thresholds for adverse cellular responses. Empirical evaluations may show consistency with thresholds, but the main evidence has to come from mechanistic considerations.Objectives: Cellular response behaviors depend on the molecular pathway and circuitry in the cell and the manner in which chemicals perturb these circuits. Understanding circuit structures that are inherently capable of resisting small perturbations and producing threshold responses is an important step towards mechanistically interpreting in vitro testing data.Methods: Here we have examined dose–response characteristics for several biochemical network motifs. These network motifs are basic building blocks of molecular circuits underpinning a variety of cellular functions, including adaptation, homeostasis, proliferation, differentiation, and apoptosis. For each motif, we present biological examples and models to illustrate how thresholds arise from specific network structures.Discussion and Conclusion: Integral feedback, feedforward, and transcritical bifurcation motifs can generate thresholds. Other motifs (e.g., proportional feedback and ultrasensitivity)produce responses where the slope in the low-dose region is small and stays close to the baseline. Feedforward control may lead to nonmonotonic or hormetic responses. We conclude that network motifs provide a basis for understanding thresholds for cellular responses. Computational pathway modeling of these motifs and their combinations occurring in molecular signaling networks will be a key element in new risk assessment approaches based on in vitro cellular assays.Citation: Zhang Q, Bhattacharya S, Conolly RB, Clewell HJ III, Kaminski NE, Andersen ME. 2014. Molecular signaling network motifs provide a mechanistic basis for cellular threshold responses. Environ Health Perspect 122:1261–1270; http://dx.doi.org/10.1289/ehp.1408244

show abstract

An investigation of spatial signal transduction in cellular networks

Cited by 11 publications

References 54 publications

Adaptive information processing of network modules to dynamic and spatial stimuli

Adaptive information processing of network modules to dynamic and spatial stimuli

Covalent Modification Cycles through the Spatial Prism

Molecular Signaling Network Motifs Provide a Mechanistic Basis for Cellular Threshold Responses

Contact Info

Product

Resources

About