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INTRODUCTION: Physicians are often required to make treatment decisions for patients with Crohn's disease on the basis of limited objective information about the state of the patient's gastrointestinal tissue while aiming to achieve mucosal healing. Tools to predict changes in mucosal health with treatment are needed. We evaluated a computational approach integrating a mechanistic model of Crohn's disease with a responder classifier to predict temporal changes in mucosal health. METHODS: A hybrid mechanistic-statistical platform was developed to predict biomarker and tissue health time courses in patients with Crohn's disease. Eligible patients from the VERSIFY study (n = 69) were classified into archetypical response cohorts using a decision tree based on early treatment data and baseline characteristics. A virtual patient matching algorithm assigned a digital twin to each patient from their corresponding response cohort. The digital twin was used to forecast response to treatment using the mechanistic model. RESULTS: The responder classifier predicted endoscopic remission and mucosal healing for treatment with vedolizumab over 26 weeks, with overall sensitivities of 80% and 75% and overall specificities of 69% and 70%, respectively. Predictions for changes in tissue damage over time in the validation set (n = 31), a measure of the overall performance of the platform, were considered good (at least 70% of data points matched), fair (at least 50%), and poor (less than 50%) for 71%, 23%, and 6% of patients, respectively. CONCLUSION: Hybrid computational tools including mechanistic components represent a promising form of decision support that can predict outcomes and patient progress in Crohn's disease.
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Doença de Crohn , Estudos de Coortes , Doença de Crohn/complicações , Doença de Crohn/tratamento farmacológico , Humanos , Mucosa Intestinal , Resultado do Tratamento , CicatrizaçãoRESUMO
Small molecule approaches targeting the nuclear factor kappa B (NF-kB) pathway, a regulator of inflammation, have thus far proven unsuccessful in the clinic in part due to the complex pleiotropic nature of this network. Downstream effects depend on multiple factors including stimulus-specific temporal patterns of NF-kB activity. Despite considerable advances, genome-level impact of changes in temporal NF-kB activity caused by inhibitors and their stimulus dependency remains unexplored. This study evaluates the effects of pathway inhibitors on early NF-κB activity and downstream gene transcription. 3T3 fibroblasts were treated with SC-514, an inhibitor targeted to the NF-kB pathway, prior to stimulation with interleukin 1 beta (IL-1ß) or tumor necrosis factor alpha (TNF-α). Stimulus induced NF-κB activation was quantified using immunofluorescence imaging over 90-minutes and gene expression tracked over 6-hours using mRNA TagSeq. When stimulated with IL-1ß or TNF-α, significant differences (Pâ¯<â¯0.05, two-way ANOVA), were observed in the temporal profiles of NF-κB activation between treated and untreated cells. Increasing numbers of differentially expressed genes (Pâ¯<â¯0.01) were observed at higher inhibitor concentrations. Individual gene expression profiles varied in an inhibitor concentration and stimulus-dependent manner. The results in this study demonstrate small molecule inhibitors acting on pleiotropic pathway components can alter signal dynamics in a stimulus-dependent manner and affect gene response in complex ways.
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Quinase I-kappa B/antagonistas & inibidores , Inflamação/metabolismo , Interleucina-1beta/metabolismo , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Células 3T3 , Animais , Expressão Gênica , Regulação da Expressão Gênica , Camundongos , Transdução de SinaisRESUMO
Receptor internalization by endocytosis regulates diverse cellular processes, from the rate of nutrient uptake to the timescale of essential signaling events. The established view is that internalization is tightly controlled by specific protein-binding interactions. However, recent work suggests that physical aspects of receptors influence the process in ways that cannot be explained by biochemistry alone. Specifically, work from several groups suggests that increasing the steric bulk of receptors may inhibit their uptake by multiple types of trafficking vesicles. How do biochemical and biophysical factors work together to control internalization? Here, we show that receptor uptake is well described by a thermodynamic trade-off between receptor-vesicle binding energy and the entropic cost of confining receptors within endocytic vesicles. Specifically, using large ligands to acutely increase the size of engineered variants of the transferrin receptor, we demonstrate that an increase in the steric bulk of a receptor dramatically decreases its probability of uptake by clathrin-coated structures. Further, in agreement with a simple thermodynamic analysis, all data collapse onto a single trend relating fractional occupancy of the endocytic structure to fractional occupancy of the surrounding plasma membrane, independent of receptor size. This fundamental scaling law provides a simple tool for predicting the impact of receptor expression level, steric bulk, and the size of endocytic structures on receptor uptake. More broadly, this work suggests that bulky ligands could be used to drive the accumulation of specific receptors at the plasma membrane surface, providing a biophysical tool for targeted modulation of signaling and metabolism from outside the cell.
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Endocitose , Entropia , Modelos Biológicos , Engenharia de Proteínas , Linhagem Celular , Humanos , Cinética , Ligantes , Ligação ProteicaRESUMO
Combinatorial control of gene expression is presumed to be mediated by molecular interactions between coincident transcription factors (TFs). While information on the genome-wide locations of TFs is available, the genes they regulate and whether they function combinatorially often remain open questions. Here, we developed a mechanistic, rather than statistical, modeling approach to elucidate TF control logic from gene expression data. Applying this approach to hundreds of genes in 85 datasets measuring the transcriptional responses of murine fibroblasts and macrophages to cytokines and pathogens, we found that stimulus-responsive TFs generally function sequentially in logical OR gates or singly. Logical AND gates were found between NF-κB-responsive mRNA synthesis and MAPKp38-responsive control of mRNA half-life, but not between temporally coincident TFs. Our analyses identified the functional target genes of each of the pathogen-responsive TFs and prompt a revision of the conceptual underpinnings of combinatorial control of gene expression to include sequentially acting molecular mechanisms that govern mRNA synthesis and decay.
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Transcrição Gênica/genética , Transcrição Gênica/fisiologia , Animais , Simulação por Computador , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/genética , Redes Reguladoras de Genes/genética , Humanos , Modelos Biológicos , Ligação Proteica , Fatores de Transcrição/genética , Ativação Transcricional/genética , Ativação Transcricional/fisiologiaRESUMO
Transcription factor nuclear factor kappa B (NF-κB) shows cooperative switch-like activation followed by prolonged oscillatory nuclear translocation in response to extracellular stimuli. These dynamics are important for activation of the NF-κB transcriptional machinery, however, NF-κB activity regulated by coordinated actions of these dynamics has not been elucidated at the system level. Using a variety of B cells with artificially rewired NF-κB signaling networks, we show that oscillations and switch-like activation of NF-κB can be dissected and that, under some conditions, these two behaviors are separated upon antigen receptor activation. Comprehensive quantitative experiments and mathematical analysis showed that the functional role of switch activation in the NF-κB system is to overcome transient IKK (IκB kinase) activity to amplify nuclear translocation of NF-κB, thereby inducing the prolonged NF-κB oscillatory behavior necessary for target gene expression and B-cell activation.
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The magnitude, duration and oscillation of cellular signalling pathway responses are often limited by negative feedback loops, defined as an 'activator-induced inhibitor' regulatory motif. Within the NFκB signalling pathway, a key negative feedback regulator is IκBα. We show here that, contrary to current understanding, NFκB-inducible expression is not sufficient for providing effective negative feedback. We then employ computational simulations of NFκB signalling to identify IκBα molecular properties that are critical for proper negative feedback control and test the resulting predictions in biochemical and single-cell live-imaging studies. We identified nuclear import and nuclear export of IκBα and the IκBα-NFκB complex, as well as the free IκBα half-life, as key determinants of post-induction repression of NFκB and the potential for subsequent reactivation. Our work emphasizes that negative feedback is an emergent systems property determined by multiple molecular and biophysical properties in addition to the required 'activator-induced inhibitor' relationship.
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Simulação por Computador , Fibroblastos/metabolismo , Regulação da Expressão Gênica/fisiologia , Quinase I-kappa B/metabolismo , Modelos Biológicos , Transdução de Sinais/fisiologia , Motivos de Aminoácidos , Animais , Fibroblastos/citologia , Quinase I-kappa B/genética , Camundongos , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismoRESUMO
Development and function of the immune system depends on cells exchanging information between themselves and with their environment. This information is processed and integrated by complex signal transduction and gene regulatory networks with rich temporal dynamics. A growing body of evidence points to a combination of network topology and temporal dynamics as a fundamental link between stimulus and function. Recent findings also bring cellular variability and stochastic events to the forefront as additional determinants of cell population responses to immune cues. In this article, we review examples of how the trinity of network topology, temporal dynamics, and cellular variability together determine the immune function. In particular we focus on Nuclear Factor kappa-B and T-cell receptor signaling networks as they have proven fertile ground for studying how function arises from the combination of topology, dynamics, and variability in a context of great clinical importance.
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Redes Reguladoras de Genes/imunologia , Interação Gene-Ambiente , NF-kappa B/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/imunologia , Animais , Humanos , NF-kappa B/genética , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genéticaRESUMO
A switchlike response in nuclear factor-κB (NF-κB) activity implies the existence of a threshold in the NF-κB signaling module. We show that the CARD-containing MAGUK protein 1 (CARMA1, also called CARD11)-TAK1 (MAP3K7)-inhibitor of NF-κB (IκB) kinase-ß (IKKß) module is a switch mechanism for NF-κB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKß to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKß target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-κB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.
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Proteínas Adaptadoras de Sinalização CARD/metabolismo , Guanilato Ciclase/metabolismo , Quinase I-kappa B/metabolismo , MAP Quinase Quinase Quinases/metabolismo , NF-kappa B/agonistas , Receptores de Antígenos de Linfócitos B/metabolismo , Animais , Linfócitos B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/genética , Linhagem Celular , Galinhas , Retroalimentação Fisiológica , Guanilato Ciclase/genética , MAP Quinase Quinase Quinases/genética , Camundongos , Camundongos Knockout , Mutação , Fosforilação , Receptores de Antígenos de Linfócitos B/genética , Serina/genética , Serina/metabolismo , Transdução de SinaisRESUMO
Highly networked signaling hubs are often associated with disease, but targeting them pharmacologically has largely been unsuccessful in the clinic because of their functional pleiotropy. Motivated by the hypothesis that a dynamic signaling code confers functional specificity, we investigated whether dynamic features may be targeted pharmacologically to achieve therapeutic specificity. With a virtual screen, we identified combinations of signaling hub topologies and dynamic signal profiles that are amenable to selective inhibition. Mathematical analysis revealed principles that may guide stimulus-specific inhibition of signaling hubs, even in the absence of detailed mathematical models. Using the NFκB signaling module as a test bed, we identified perturbations that selectively affect the response to cytokines or pathogen components. Together, our results demonstrate that the dynamics of signaling may serve as a pharmacological target, and we reveal principles that delineate the opportunities and constraints of developing stimulus-specific therapeutic agents aimed at pleiotropic signaling hubs.
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Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos , Animais , Simulação por Computador , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Humanos , NF-kappa B/metabolismoRESUMO
NF-κB plays a vital role in cellular immune and inflammatory response, survival, and proliferation by regulating the transcription of various genes involved in these processes. To activate transcription, RelA (a prominent NF-κB family member) interacts with transcriptional co-activators like CREB-binding protein (CBP) and its paralog p300 in addition to its cognate κB sites on the promoter/enhancer regions of DNA. The RelA:CBP/p300 complex is comprised of two components--first, DNA binding domain of RelA interacts with the KIX domain of CBP/p300, and second, the transcriptional activation domain (TAD) of RelA binds to the TAZ1 domain of CBP/p300. A phosphorylation event of a well-conserved RelA(Ser276) is prerequisite for the former interaction to occur and is considered a decisive factor for the overall RelA:CBP/p300 interaction. The role of the latter interaction in the transcription of RelA-activated genes remains unclear. Here we provide the solution structure of the latter component of the RelA:CBP complex by NMR spectroscopy. The structure reveals the folding of RelA-TA2 (a section of TAD) upon binding to TAZ1 through its well-conserved hydrophobic sites in a series of grooves on the TAZ1 surface. The structural analysis coupled with the mechanistic studies by mutational and isothermal calorimetric analyses allowed the design of RelA-mutants that selectively abrogated the two distinct components of the RelA:CBP/p300 interaction. Detailed studies of these RelA mutants using cell-based techniques, mathematical modeling, and genome-wide gene expression analysis showed that a major set of the RelA-activated genes, larger than previously believed, is affected by this interaction. We further show how the RelA:CBP/p300 interaction controls the nuclear response of NF-κB through the negative feedback loop of NF-κB pathway. Additionally, chromatin analyses of RelA target gene promoters showed constitutive recruitment of CBP/p300, thus indicating a possible role of CBP/p300 in recruitment of RelA to its target promoter sites.
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Proteína p300 Associada a E1A/metabolismo , Proteínas de Membrana/metabolismo , NF-kappa B/metabolismo , Fosfoproteínas/metabolismo , Fator de Transcrição RelA/metabolismo , Células 3T3 , Sequência de Aminoácidos , Animais , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células , Proteína p300 Associada a E1A/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Interações Hidrofóbicas e Hidrofílicas , Espectroscopia de Ressonância Magnética , Proteínas de Membrana/genética , Camundongos , Dados de Sequência Molecular , NF-kappa B/genética , Fosfoproteínas/genética , Fosforilação , Regiões Promotoras Genéticas , Ligação Proteica , Dobramento de Proteína , Estrutura Terciária de Proteína , Fator de Transcrição RelA/genética , Transcrição GênicaRESUMO
The transcription factor NFκB, a key component of the immune system, shows intricate stimulus-specific temporal dynamics. Those dynamics are thought to play a role in controlling the physiological response to cytokines and pathogens. Biochemical evidence suggests that the NFκB inducing kinase, IKK, a signaling hub onto which many signaling pathways converge, is regulated via a regulatory cycle comprising a poised, an active, and an inactive state. We hypothesize that it operates as a modulator of signal dynamics, actively reshaping the signals generated at the receptor proximal level. Here we show that a regulatory cycle can function in at least three dynamical regimes, tunable by regulating a single kinetic parameter. In particular, the simplest three-state regulatory cycle can generate signals with two well-defined phases, each with distinct coding capabilities in terms of the information they can carry about the stimulus. We also demonstrate that such a kinase cycle can function as a signal categorizer classifying diverse incoming signals into outputs with a limited set of temporal activity profiles. Finally, we discuss the extension of the results to other regulatory motifs that could be understood in terms of the regimes of the three-state cycle.
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Quinase I-kappa B/metabolismo , Modelos Biológicos , Transdução de Sinais , Ativação EnzimáticaRESUMO
Besides activating NFκB by phosphorylating IκBs, IKKα/IKKß kinases are also involved in regulating metabolic insulin signaling, the mTOR pathway, Wnt signaling, and autophagy. How IKKß enzymatic activity is targeted to stimulus-specific substrates has remained unclear. We show here that NEMO, known to be essential for IKKß activation by inflammatory stimuli, is also a specificity factor that directs IKKß activity toward IκBα. Physical interaction and functional competition studies with mutant NEMO and IκB proteins indicate that NEMO functions as a scaffold to recruit IκBα to IKKß. Interestingly, expression of NEMO mutants that allow for IKKß activation by the cytokine IL-1, but fail to recruit IκBs, results in hyperphosphorylation of alternative IKKß substrates. Furthermore IKK's function in autophagy, which is independent of NFκB, is significantly enhanced without NEMO as IκB scaffold. Our work establishes a role for scaffolds such as NEMO in determining stimulus-specific signal transduction via the pleiotropic signaling hub IKK.
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Quinase I-kappa B/metabolismo , Proteínas I-kappa B/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transdução de Sinais , Células 3T3 , Animais , Autofagia/efeitos dos fármacos , Western Blotting , Células HEK293 , Humanos , Quinase I-kappa B/genética , Proteínas I-kappa B/genética , Interleucina-1/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , Complexos Multiproteicos/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Ligação ProteicaRESUMO
Mathematical modeling has proved to be a critically important approach in the study of many complex networks and dynamic systems in physics, engineering, chemistry, and biology. The nuclear factor κB (NF-κB) system consists of more than 50 proteins and protein complexes and is both a highly networked and dynamic system. To date, mathematical modeling has only addressed a small fraction of the molecular species and their regulation, but when employed in conjunction with experimental analysis has already led to important insights. Here, we provide a personal account of studying how the NF-κB signaling system functions using mathematical descriptions of the molecular mechanisms. We focus on the insights gained about some of the key regulatory components: the control of the steady state, the signaling dynamics, and signaling crosstalk. We also discuss the biological relevance of these regulatory systems properties.
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Modelos Biológicos , NF-kappa B/metabolismo , Transdução de Sinais , Animais , Humanos , Subunidade p50 de NF-kappa B/metabolismo , Fator de Transcrição RelA/metabolismoRESUMO
The maintenance and detection of signaling gradients are critical for proper development and cell migration. In single-cell organisms, gradient detection allows cells to orient toward a distant mating partner or nutrient source. Budding yeast expand their growth toward mating pheromone gradients through a process known as chemotropic growth. MATα cells secrete α-factor pheromone that stimulates chemotropism and mating differentiation in MATa cells and vice versa. Paradoxically, MATa cells secrete Bar1, a protease that degrades α-factor and that attenuates the mating response, yet is also required for efficient mating. We observed that MATa cells avoid each other during chemotropic growth. To explore this behavior, we developed a computational platform to simulate chemotropic growth. Our simulations indicated that the release of Bar1 enabled individual MATa cells to act as α-factor sinks. The simulations suggested that the resultant local reshaping of pheromone concentration created gradients that were directed away from neighboring MATa cells (self-avoidance) and that were increasingly amplified toward partners of the opposite sex during elongation. The behavior of Bar1-deficient cells in gradient chambers and mating assays supported these predictions from the simulations. Thus, budding yeast dynamically remodel their environment to ensure productive responses to an external stimulus and avoid nonproductive cell-cell interactions.
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Peptídeos/metabolismo , Proteólise , Saccharomyces cerevisiae/metabolismo , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Fator de Acasalamento , Peptídeos/genética , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismoRESUMO
The health of organisms and cells depends on appropriate responses to diverse internal and external cues, stimuli, or challenges, such as changes in hormone or cytokine levels, or exposure to a pathogen. Cellular responses must be tailored to the identity and intensity of the stimulus and therefore intra-cellular signals must carry information about both. However, signaling mediators often form intricate networks that react to multiple stimuli yet manage to produce stimulus-specific responses. The multi-functionality ('functional pleiotropism') of signaling nodes suggests that biological networks have evolved ways of passing physiologically relevant stimulus information through shared channels. Increasing evidence supports the notion that this is achieved in part through temporal regulation of signaling mediators' activities. The present challenge is to identify the features of temporal activity profile that represent information about a given stimulus and understand how cells read the temporal codes to control their responses.
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Espaço Intracelular , Transdução de Sinais , Animais , Regulação da Expressão GênicaRESUMO
The cellular response elicited by an environmental cue typically varies with the strength of the stimulus. For example, in the yeast Saccharomyces cerevisiae, the concentration of mating pheromone determines whether cells undergo vegetative growth, chemotropic growth, or mating. This implies that the signaling pathways responsible for detecting the stimulus and initiating a response must transmit quantitative information about the intensity of the signal. Our previous experimental results suggest that yeast encode pheromone concentration as the duration of the transmitted signal. Here we use mathematical modeling to analyze possible biochemical mechanisms for performing this "dose-to-duration" conversion. We demonstrate that modulation of signal duration increases the range of stimulus concentrations for which dose-dependent responses are possible; this increased dynamic range produces the counterintuitive result of "signaling beyond saturation" in which dose-dependent responses are still possible after apparent saturation of the receptors. We propose a mechanism for dose-to-duration encoding in the yeast pheromone pathway that is consistent with current experimental observations. Most previous investigations of information processing by signaling pathways have focused on amplitude encoding without considering temporal aspects of signal transduction. Here we demonstrate that dose-to-duration encoding provides cells with an alternative mechanism for processing and transmitting quantitative information about their surrounding environment. The ability of signaling pathways to convert stimulus strength into signal duration results directly from the nonlinear nature of these systems and emphasizes the importance of considering the dynamic properties of signaling pathways when characterizing their behavior. Understanding how signaling pathways encode and transmit quantitative information about the external environment will not only deepen our understanding of these systems but also provide insight into how to reestablish proper function of pathways that have become dysregulated by disease.
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Modelos Biológicos , Transdução de Sinais/fisiologia , Biologia Computacional , Relação Dose-Resposta a Droga , Retroalimentação Fisiológica , Feromônios/administração & dosagem , Feromônios/fisiologia , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/fisiologia , Receptores de Feromônios/efeitos dos fármacos , Receptores de Feromônios/fisiologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/fisiologia , Proteínas de Saccharomyces cerevisiae/fisiologia , Transdução de Sinais/efeitos dos fármacos , Fatores de TempoRESUMO
Cell differentiation requires the ability to detect and respond appropriately to a variety of extracellular signals. Here we investigate a differentiation switch induced by changes in the concentration of a single stimulus. Yeast cells exposed to high doses of mating pheromone undergo cell division arrest. Cells at intermediate doses become elongated and divide in the direction of a pheromone gradient (chemotropic growth). Either of the pheromone-responsive MAP kinases, Fus3 and Kss1, promotes cell elongation, but only Fus3 promotes chemotropic growth. Whereas Kss1 is activated rapidly and with a graded dose-response profile, Fus3 is activated slowly and exhibits a steeper dose-response relationship (ultrasensitivity). Fus3 activity requires the scaffold protein Ste5; when binding to Ste5 is abrogated, Fus3 behaves like Kss1, and the cells no longer respond to a gradient or mate efficiently with distant partners. We propose that scaffold proteins serve to modulate the temporal and dose-response behavior of the MAP kinase.
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Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/enzimologia , Diferenciação Celular/efeitos dos fármacos , Ativação Enzimática , Feromônios/farmacologia , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimentoRESUMO
Intracellular signaling pathways that share common components often elicit distinct physiological responses. In most cases, the biochemical mechanisms responsible for this signal specificity remain poorly understood. Protein scaffolds and cross-inhibition have been proposed as strategies to prevent unwanted cross-talk. Here, we report a mechanism for signal specificity termed "kinetic insulation." In this approach signals are selectively transmitted through the appropriate pathway based on their temporal profile. In particular, we demonstrate how pathway architectures downstream of a common component can be designed to efficiently separate transient signals from signals that increase slowly over time. Furthermore, we demonstrate that upstream signaling proteins can generate the appropriate input to the common pathway component regardless of the temporal profile of the external stimulus. Our results suggest that multilevel signaling cascades may have evolved to modulate the temporal profile of pathway activity so that stimulus information can be efficiently encoded and transmitted while ensuring signal specificity.
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Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Modelos Biológicos , Transdução de Sinais/fisiologia , Fenômenos Biofísicos , Biofísica , Cinética , Sistema de Sinalização das MAP Quinases/fisiologiaRESUMO
We perform a systematic analysis of mechanisms of feedback regulation that underlie short-term adaptation in intracellular signaling systems. Upon receiving an external cue, these systems generate a transient response that quickly returns to basal levels even if the stimulus persists. Signaling pathways capable of short-term adaptation are found in systems as diverse as the high osmolarity response of yeast, gradient sensing in Dictyostelium, and the cytokine response in vertebrates. Using mathematical analysis and computational experiments, we compare different feedback architectures in terms of response amplitude and duration, ability to adapt, and response to variable stimulus levels. Our analysis reveals three important features of these systems: 1), multiple step signaling cascades improve sensitivity to low doses by an effect distinct from signal amplification; 2), some feedback architectures act as signal transducers converting stimulus strength into response duration; and 3), feedback deactivation acts as a dose-dependent switch between transient and sustained responses. Finally, we present characteristic features for each form of feedback regulation that can aid in their identification.