Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling.
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ABSTRACT:
SUBMITTER: Billing U
PROVIDER: S-EPMC6338669 | biostudies-other | 2019
REPOSITORIES: biostudies-other
Publications
Robustness and Information Transfer within IL-6-induced JAK/STAT Signalling.
Billing Ulrike U Jetka Tomasz T Nortmann Lukas L Wundrack Nicole N Komorowski Michal M Waldherr Steffen S Schaper Fred F Dittrich Anna A
Communications biology 20190118
Cellular communication via intracellular signalling pathways is crucial. Expression and activation of signalling proteins is heterogenous between isogenic cells of the same cell-type. However, mechanisms evolved to enable sufficient communication and to ensure cellular functions. We use information theory to clarify mechanisms facilitating IL-6-induced JAK/STAT signalling despite cell-to-cell variability. We show that different mechanisms enabling robustness against variability complement each o ...[more]
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Project description:BackgroundCell-to-cell heterogeneity is an inherent feature of multicellular organisms and is central in all physiological and pathophysiological processes including cellular signal transduction. The cytokine IL-6 is an essential mediator of pro- and anti-inflammatory processes. Dysregulated IL-6-induced intracellular JAK/STAT signalling is associated with severe inflammatory and proliferative diseases. Under physiological conditions JAK/STAT signalling is rigorously controlled and timely orchestrated by regulatory mechanisms such as expression of the feedback-inhibitor SOCS3 and activation of the protein-tyrosine phosphatase SHP2 (PTPN11). Interestingly, the function of negative regulators seems not to be restricted to controlling the strength and timely orchestration of IL-6-induced STAT3 activation. Exemplarily, SOCS3 increases robustness of late IL-6-induced STAT3 activation against heterogenous STAT3 expression and reduces the amount of information transferred through JAK/STAT signalling.MethodsHere we use multiplexed single-cell analyses and information theoretic approaches to clarify whether also SHP2 contributes to robustness of STAT3 activation and whether SHP2 affects the amount of information transferred through IL-6-induced JAK/STAT signalling.ResultsSHP2 increases robustness of both basal, cytokine-independent STAT3 activation and early IL-6-induced STAT3 activation against differential STAT3 expression. However, SHP2 does not affect robustness of late IL-6-induced STAT3 activation. In contrast to SOCS3, SHP2 increases the amount of information transferred through IL-6-induced JAK/STAT signalling, probably by reducing cytokine-independent STAT3 activation and thereby increasing sensitivity of the cells. These effects are independent of SHP2-dependent MAPK activation.ConclusionIn summary, the results of this study extend our knowledge of the functions of SHP2 in IL-6-induced JAK/STAT signalling. SHP2 is not only a repressor of basal and cytokine-induced STAT3 activity, but also ensures robustness and transmission of information. Plain English summary Cells within a multicellular organism communicate with each other to exchange information about the environment. Communication between cells is facilitated by soluble molecules that transmit information from one cell to the other. Cytokines such as interleukin-6 are important soluble mediators that are secreted when an organism is faced with infections or inflammation. Secreted cytokines bind to receptors within the membrane of their target cells. This binding induces activation of an intracellular cascade of reactions called signal transduction, which leads to cellular responses. An important example of intracellular signal transduction is JAK/STAT signalling. In healthy organisms signalling is controlled and timed by regulatory mechanisms, whose activation results in a controlled shutdown of signalling pathways. Interestingly, not all cells within an organism are identical. They differ in the amount of proteins involved in signal transduction, such as STAT3. These differences shape cellular communication and responses to intracellular signalling. Here, we show that an important negative regulatory protein called SHP2 (or PTPN11) is not only responsible for shutting down signalling, but also for steering signalling in heterogeneous cell populations. SHP2 increases robustness of STAT3 activation against variable STAT3 amounts in individual cells. Additionally, it increases the amount of information transferred through JAK/STAT signalling by increasing the dynamic range of pathway activation in heterogeneous cell populations. This is an amazing new function of negative regulatory proteins that contributes to communication in heterogeneous multicellular organisms in health and disease. Video Abstract.
| S-EPMC8444181 | biostudies-literature
Project description:Interferons (IFN) are cytokines which, upon binding to cell surface receptors, trigger a series of downstream biochemical events including Janus Kinase (JAK) activation, phosphorylation of Signal Transducer and Activator of Transcription protein (STAT), translocation of pSTAT to the nucleus and transcriptional activation. Dysregulated IFN signalling has been linked to cancer progression and auto-immune diseases. Here, we report the serendipitous discovery of a small molecule that blocks IFNγ activation of JAK-STAT signalling. Further lead optimisation gave rise to a potent and more selective analogue that exerts its activity by a mechanism consistent with direct IFNγ targeting in vitro, which reduces bleeding in model of haemorrhagic colitis in vivo. This first-in-class small molecule also inhibits type I and III IFN-induced STAT phosphorylation in vitro. Our work provides the basis for the development of pan-IFN inhibitory drugs.
| S-EPMC9400964 | biostudies-literature
Project description:Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation. Depletion of VPS35 leads to abnormally prolonged residency and association of the IFNAR subunits at the early endosome, resulting in increased activation of STAT1- and IFN-dependent gene transcription. These experimental data establish the retromer complex as a key spatiotemporal regulator of IFNAR endosomal sorting and a new factor in type-I IFN-induced JAK/STAT signalling and gene transcription.
| S-EPMC5150223 | biostudies-literature
Project description:AimsLeft-atrial (LA) fibrosis is an important feature of many atrial fibrillation (AF) substrates. The JAK-STAT system contributes to cardiac remodelling, but its role in AF is unknown. Here we investigated JAK-STAT changes in an AF-model and their potential contributions to LA-fibrosis.Methods and resultsLA-remodelling was studied in dogs with heart failure (HF) induced by ventricular tachypacing (VTP, 240 bpm), and in mice with left-ventricular (LV) dysfunction due to myocardial infarction (MI). The selective STAT-3 inhibitor S3I-201 was administered to fibroblasts in vitro or mice in vivo (10?mg/kg/d, osmotic mini-pump). HF-dogs developed LA-selective fibrosis and AF-susceptibility at 1-week VTP. The mRNA-expression of platelet-derived growth factor (PDGF, a JAK-STAT activator) isoforms A, C and D, as well as JAK2, increased in LA fibroblasts from 1-week VTP. HF upregulated protein-expression of PDGF-receptor-? and phosphorylated (activated) signal transducer and activator of transcription 3 (STAT3) in LA. PDGF-AB stimulation of LA fibroblasts increased PDGFR-?, STAT3 and phosphorylated-STAT3 expression, as well as collagen-1 and fibronectin-1 protein secretion (by 1.6- to 20-fold), with smaller changes in LV fibroblasts. Phosphorylated-STAT3 and collagen upregulation were suppressed by the JAK2 inhibitor AG-490, PDGF receptor inhibitor AG1296 and STAT3-inhibitor SI3-201. In vivo S3I-201 treatment of MI-mice attenuated LA-fibrosis, LA-dilation and P-wave duration changes versus vehicle-control.ConclusionsHF activates the LA JAK-STAT system and enhances PDGF-signalling. JAK-STAT inhibition reduces the profibrotic effects of PDGF stimulation on canine fibroblasts in vitro while attenuating in vivo LA-fibrosis and remodelling in post-MI mice, suggesting that the JAK/STAT pathway contributes to LA-fibrogenesis and might be a potential target for LA-fibrosis prevention.
| S-EPMC5852635 | biostudies-literature
Project description:Appropriate regulation of signal transduction pathways is essential for normal development and is often disrupted in disease. Therefore, many regulatory mechanisms and feedback loops have evolved to ensure appropriate signalling. One mechanism previously suggested to modulate a range of signal transduction pathways involves the internalisation and destruction of transmembrane receptors by the endocytic trafficking machinery. Strikingly, a recent report has suggested that the endocytic trafficking of the Drosophila JAK-STAT pathway receptor Domeless (Dome) does not act to downregulate pathway activity, but rather is necessary for in vivo signalling. Here, we examine this relationship to address the interaction of Drosophila JAK-STAT pathway signalling and endocytic trafficking. We show that Dome is trafficked through clathrin-mediated endocytosis and a directed RNAi screen identified several components of the endocytic machinery as negative regulators of pathway signalling. We demonstrate that Dome signals both from the plasma membrane and internalised vesicles and show, using knockdown experiments, that endocytic components negatively regulate JAK-STAT signalling in vivo. As such, disruption in endocytic trafficking represents a potent negative regulator of the disease relevant JAK-STAT signalling cascade.
| S-EPMC2951467 | biostudies-other
Project description:Appropriately formulated quantitative computational models can support researchers in understanding the dynamic behaviour of biological pathways and support hypothesis formulation and selection by "in silico" experimentation. An obstacle to widespread adoption of this approach is the requirement to formulate a biological pathway as machine executable computer code. We have recently proposed a novel, biologically intuitive, narrative-style modelling language for biologists to formulate the pathway which is then automatically translated into an executable format and is, thus, usable for analysis via existing simulation techniques.Here we use a high-level narrative language in designing a computational model of the gp130/JAK/STAT signalling pathway and show that the model reproduces the dynamic behaviour of the pathway derived by biological observation. We then "experiment" on the model by simulation and sensitivity analysis to define those parameters which dominate the dynamic behaviour of the pathway. The model predicts that nuclear compartmentalisation and phosphorylation status of STAT are key determinants of the pathway and that alternative mechanisms of signal attenuation exert their influence on different timescales.The described narrative model of the gp130/JAK/STAT pathway represents an interesting case study showing how, by using this approach, researchers can model biological systems without explicitly dealing with formal notations and mathematical expressions (typically used for biochemical modelling), nevertheless being able to obtain simulation and analysis results. We present the model and the sensitivity analysis results we have obtained, that allow us to identify the parameters which are most sensitive to perturbations. The results, which are shown to be in agreement with existing mathematical models of the gp130/JAK/STAT pathway, serve us as a form of validation of the model and of the approach itself.
| S-EPMC2678071 | biostudies-literature
Project description:ObjectiveDuring rheumatoid arthritis (RA), the angiogenic processes, occurring with pannus-formation, may be a therapeutic target. JAK/STAT-pathway may play a role and the aim of this work was to investigate the inhibiting role of a JAK-inhibitor, tofacitinib, on the angiogenic mechanisms occurring during RA.MethodsAfter ethical approval, JAK-1, JAK-3, STAT-1, STAT-3 and VEGF expression was evaluated on RA-synovial-tissues. In vitro, endothelial cells (ECs), stimulated with 20 ng/ml of VEGF and/or 1 μM of tofacitinib, were assessed for tube formation, migration and proliferation, by Matrigel, Boyden chamber assay and ki67 gene-expression. In vivo, 32 mice received collagen (collagen-induced arthritis (CIA)) and 32 mice PBS (control). At day 19, CIA and controls mice were divided: 16 mice receiving vehicle and 16 mice receiving tofacitinib. At day 35, the arthritis score, the thickness of paw joints and the serum levels of VEGF and Ang-2 were evaluated.ResultsThe expression of JAK-1, JAK-3, STAT-1, STAT-3 and VEGF in synovial tissue of RA-patients were significantly higher than healthy controls. In vitro, tofacitinib inhibited the ECs ability to form vessels, to proliferate and to migrate. In vivo, administration of tofacitinib prevented the increase of the arthritis score, the paw thickness, the synovial vessels and VEGF and Ang-2 serum-accumulation, when compared to CIA without tofacitinib.ConclusionsWe explored the anti-angiogenic role of tofacitinib, reporting its ability to inhibit in vitro the angiogenic mechanisms of ECs and in vivo the formation of new synovial vessels, occurring in CIA model. These findings suggest that the therapeutic effect of tofacitinib during RA may be also related to its anti-angiogenic activity.
| S-EPMC8364029 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) is increasing worldwide, and it is associated with increased risk of coronary artery disease (CAD). For T2DM patients, the main surgical intervention for CAD is autologous saphenous vein grafting. However, T2DM patients have increased risk of saphenous vein graft failure (SVGF). While the mechanisms underlying increased risk of vascular disease in T2DM are not fully understood, hyperglycaemia, insulin resistance, and hyperinsulinaemia have been shown to contribute to microvascular damage, whereas clinical trials have reported limited effects of intensive glycaemic control in the management of macrovascular complications. This suggests that factors other than glucose exposure may be responsible for the macrovascular complications observed in T2DM. SVGF is characterised by neointimal hyperplasia (NIH) arising from endothelial cell (EC) dysfunction and uncontrolled migration and proliferation of vascular smooth muscle cells (SMCs). This is driven in part by proinflammatory cytokines released from the activated ECs and SMCs, particularly interleukin 6 (IL-6). IL-6 stimulation of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT) pathway is a key mechanism through which EC inflammation, SMC migration, and proliferation are controlled and whose activation might therefore be enhanced in patients with T2DM. In this review, we investigate how proinflammatory cytokines, particularly IL-6, contribute to vascular damage resulting in SVGF and how suppression of proinflammatory cytokine responses via targeting the JAK/STAT pathway could be exploited as a potential therapeutic strategy. These include the targeting of suppressor of cytokine signalling (SOCS3), which appears to play a key role in suppressing unwanted vascular inflammation, SMC migration, and proliferation.
| S-EPMC6334365 | biostudies-literature
Project description:The family of cytokines signalling through the common receptor subunit gp130 comprises interleukin (IL)-6, IL-11, leukaemia inhibitory factor, oncostatin M, ciliary neurotrophic factor and cardiotrophin-1. These so-called IL-6-type cytokines play an important role in the regulation of complex cellular processes such as gene activation, proliferation and differentiation. The current knowledge on the signal-transduction mechanisms of these cytokines from the plasma membrane to the nucleus is reviewed. In particular, we focus on the assembly of receptor complexes after ligand binding, the activation of receptor-associated kinases of the Janus family, and the recruitment and phosphorylation of transcription factors of the STAT family, which dimerize, translocate to the nucleus, and bind to enhancer elements of respective target genes leading to transcriptional activation. The important players in the signalling pathway, namely the cytokines and the receptor components, the Janus kinases Jak1, Jak2 and Tyk2, the signal transducers and activators of transcription STAT1 and STAT3 and the tyrosine phosphatase SHP2 [SH2 (Src homology 2) domain-containing tyrosine phosphatase] are introduced and their structural/functional properties are discussed. Furthermore, we review various mechanisms involved in the termination of the IL-6-type cytokine signalling, namely the action of tyrosine phosphatases, proteasome, Jak kinase inhibitors SOCS (suppressor of cytokine signalling), protein inhibitors of activated STATs (PIAS), and internalization of the cytokine receptors via gp130. Although all IL-6-type cytokines signal through the gp130/Jak/STAT pathway, the comparison of their physiological properties shows that they elicit not only similar, but also distinct, biological responses. This is reflected in the different phenotypes of IL-6-type-cytokine knock-out animals.
| S-EPMC1219691 | biostudies-other
Project description:Growth factor and cytokine signaling can influence the development of several cancer types. One of the key players in the development of cancer is the Janus kinas (JAK) signal transducer of activators of transcription (STAT) signaling pathway. The majority of growth factors and cytokine interactions with their membrane-bound receptors trigger JAK-STAT activation. The influential relationship between obesity and cancer is a fact. However, there is a complex sequence of events contributing to the regulation of this mechanism to promote tumor growth, yet to be fully elucidated. The JAK-STAT pathway is influenced by obesity-associated changes that have been shown to impact cancer growth and progression. This intricate process is highly regulated by a vast array of adipokines and cytokines that exert their pleiotropic effects on cancer cells to enhance metastasis to distant target sites. Leptin is a cytokine, or more precise, an adipokine secreted mainly by adipose tissue that requires JAK-STAT activation to exert its biological functions. Leptin is the central regulator of energy balance and appetite. Leptin binding to its receptor OB-R in turn activates JAK-STAT, which induces proliferation, angiogenesis, and anti-apoptotic events in normal cells and malignant cells expressing the receptor. Leptin also induces crosstalk with Notch and IL-1 (NILCO), which involves other angiogenic factors promoting tumor growth. Therefore, the existence of multiple novel classes of therapeutics that target the JAK/STAT pathway has significant clinical implications. Then, the identification of the signaling networks and factors that regulate the obesity-cancer link to which potential pharmacologic interventions can be implemented to inhibit tumor growth and metastasis. In this review, we will discuss the specific relationship between leptin-JAK-STAT signaling and cancer.
| S-EPMC5041020 | biostudies-literature