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.
View Article and Find Full Text PDFSmall 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.
View Article and Find Full Text PDFReceptor 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.
View Article and Find Full Text PDFTranscription 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.
View Article and Find Full Text PDFCombinatorial 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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFWiley Interdiscip Rev Syst Biol Med
June 2016
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.
View Article and Find Full Text PDFA 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-β (IKKβ) 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 IKKβ to TAK1, generating a steep dose response to BCR stimulation.
View Article and Find Full Text PDFHighly 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.
View Article and Find Full Text PDFNF-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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFBesides activating NFκB by phosphorylating IκBs, IKKα/IKKβ kinases are also involved in regulating metabolic insulin signaling, the mTOR pathway, Wnt signaling, and autophagy. How IKKβ enzymatic activity is targeted to stimulus-specific substrates has remained unclear. We show here that NEMO, known to be essential for IKKβ activation by inflammatory stimuli, is also a specificity factor that directs IKKβ activity toward IκBα.
View Article and Find Full Text PDFMathematical 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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFThe 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.
View Article and Find Full Text PDFCell 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.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
October 2007
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.
View Article and Find Full Text PDFWe 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.
View Article and Find Full Text PDFBackground: A common property of signal transduction systems is that they rapidly lose their ability to respond to a given stimulus. For instance in yeast, the mitogen-activated protein (MAP) kinase Hog1 is activated and inactivated within minutes, even when the osmotic-stress stimulus is sustained.
Results: Here, we used a combination of experimental and computational analyses to investigate the dynamic behavior of Hog1 activation in vivo.