Crosstalk in nf b signaling pathways pdf

As a specific use case, we asked whether one pathway could activate or inhibit another using the same mediating protein. We list these pathway pairs on the statistics page on the website. Computational methods can identify crosstalk automatically 24 , 27 — We previously used an early version of XTalkDB as a gold standard for the evaluation of three such methods Therein we discovered that the commonly-held conjecture that crosstalk occurs when two pathways share proteins is a poor predictor: it achieved an area under the ROC curve AUC equal to that of the random classifier.

Moreover, a method that relied on interactions that connect proteins in one pathway to another 28 performed only a little better; note that SignaLink 2. A novel path-based technique that we developed had superior AUC. The inclusion of both positive pathway pairs with crosstalk supported in the literature and negative pairs for whom we could not find evidence for crosstalk examples in XTalkDB was critical to the success of the evaluation.

We expect that XTalkDB will continue to serve as a powerful resource for evaluating the accuracy of such computational methods. Aberrant signaling has been observed in cancers, developmental disorders, and neurodegenerative diseases 7 — Additionally, unexpected drug side effects have been associated with non-canonical signaling events 30 , XTalkDB provides protein mediators of crosstalk that may be used to better understand these processes, especially in combination with algorithms that systematically integrate protein interaction and signaling networks with experimental data on drugs and their effects 30 , We are planning to expand XTalkDB in several ways.

First, we will provide XTalkDB for download in additional computable formats. BEL is a promising option since it is designed to represent scientific findings by capturing causal and correlative relationships at the levels of molecular events and cellular processes. Second, we will store additional types of information about each crosstalking pair of pathways in order to provide a more comprehensive description of these events.

It is well known that signal transduction pathways rely on post-translational modifications PTMs to determine protein activities. Therefore, we will document PTMs that participate and mediate the crosstalk between pathways.

Third, we will increase the number of pathways we cover, e. Including these categories will increase the scope of XTalkDB beyond signaling pathways and diversify its repertoire of crosstalk events. However, the manual curation process underlying XTalkDB has its limitations Supplementary Section 2 , especially as we seek to expand the coverage of the database: the number of pairs to be curated grows quadratically with the number of pathways.

Hence, our final direction will be to use text mining as a means to augment and accelerate manual curation. Specifically, we plan to develop a natural-language processing NLP framework that will rate publications based on their likelihood to document crosstalk. XTalkDB contains the specific sentence documenting the crosstalk in each supporting publication.

In several cases, XTalkDB also includes sentences that are suggesting of crosstalk but are ultimately misleading. These data promise to be very useful for training NLP systems for automatically curating the literature for instances of crosstalk.

Crosstalk is a widely studied phenomenon that has been observed in both healthy and disease states, across multiple tissues and in several species. We were surprised to find that almost half the pathway pairs in XTalkDB have literature evidence supporting their crosstalk.

This high degree of crosstalk emphasizes the complex nature of cellular signaling. This database may spur research on relationships between signaling pathways and how they are defined.

As far as we are aware, XTalkDB is a unique resource that is not replicated by any other database. We expect XTalkDB to be a valuable resource to the biomedical community. Read article at publisher's site DOI : Cancer Med , 10 22 , 02 Nov J Cell Commun Signal , 13 4 , 16 Dec Free to read. Front Pharmacol , , 11 Jun J Cell Biochem , 6 , 23 Dec Cited by: 12 articles PMID: Environ Toxicol Chem , 37 6 , 07 May To arrive at the top five similar articles we use a word-weighted algorithm to compare words from the Title and Abstract of each citation.

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Share this article Share with email Share with twitter Share with linkedin Share with facebook. Abstract Analysis of signaling pathways and their crosstalk is a cornerstone of systems biology. Free full text. Nucleic Acids Res. Published online Nov PMID: Sarah A. Allison N. Author information Article notes Copyright and License information Disclaimer. For commercial re-use, please contact moc. This article has been cited by other articles in PMC.

Go to:. Open in a separate window. Figure 1. The XTalkDB data model XTalkDB uses a biologically grounded principle to determine if there is crosstalk from one pathway say, A to another say, B : an experiment demonstrates that perturbing at least one protein in pathway A causes a response in or downstream of pathway B. For every pair of pathways, XTalkDB records detailed information describing the experimental conditions under which crosstalk was discovered: the PubMed id of the paper that reported the crosstalk, the direction, e.

Curation procedure For each pathway pair, we used the following procedure to manually curate and identify publications in the literature that may support their crosstalk.

Stabilization of NIK results in the stimulation of downstream noncanonical signaling events. In contrast to the canonical pathway, p is processed to p52 only after the noncanonical pathway is stimulated. There are many cellular sources of reactive oxygen species ROS within a cell Figure 1. These sources can be broadly divided into two main categories.

Firstly, there are those biological processes that release ROS as a byproduct, or a waste product, of various other necessary reactions and secondly, there are those processes that generate ROS intentionally, either in molecular synthesis or breakdown, as part of a signal transduction pathway, or as part of a cell defense mechanism. Intracellular Sources of ROS. ROS are also produced by NAD P H oxidases, sometimes in response to cytokines and other growth factor receptors, which may also utilize other pathways to produce ROS for use in their signaling pathways.

Lastly, metabolic enzymes often create ROS as side products or through nonspecific reactions. In the first category, the mitochondria are in a large measure the greatest source of ROS, since the reactions that occur during oxidative phosphorylation processes frequently lose electrons during their transfer between electron transport chain complexes. These electrons react with molecular oxygen to produce ROS.

In consequence of this, the toxic buildup of ROS and cellular oxidation is usually alleviated by enzymes such as the superoxide dismutases, catalase, and peroxiredoxins, as well as systems of antioxidants and their associated enzymes, such as the thioredoxin and glutathione systems Figure 1 13 , 14 , These systems not only serve to repair oxidative damage, but also contribute to the overall response of the cell to ROS by acting as oxidative sensors in signal transduction pathways.

For instance, thioredoxin-1 oxidation has been proposed to serve in translating information on the redox state of the cell into ASK1 kinase activity through various mechanisms 16 , 17 , 18 , 19 , This superoxide is typically used as a defense tool against infectious pathogens, and is converted in phagosomal compartments by superoxide dismutase and myeloperoxidase to hypochlorous acid HOCl , which is a potent microbicidal compound However, during this process, some leakage of ROS from the phagosome occurs; and they enter the cytosol, contributing to the oxidative stress of the cell.

In addition to their cell defense function, local recruitment of NADPH oxidases, including non-phagocytic oxidases, has more recently been implicated in the production of ROS by growth factors and cytokines, though some of these may produce ROS by other means Consequently, these ROS are generated intentionally by the cell to function specifically within signaling pathways. Likewise, other ROS-generating enzymes, such as lipoxygenases and cyclooxygenases.

As mentioned previously, ROS are toxic in cells at certain levels, due to the oxidative stress they exert by their reaction with proteins, lipids, and nucleic acids. The correct cellular response to ROS production is consequently critical in order to prevent further oxidative damage, and to maintain cell survival. However, when too much cellular damage has occurred, it is to the advantage of a multicellular organism to remove the cell for the benefit of the surrounding cells. Reactive oxygen species can therefore trigger both apoptotic and necrotic cell death depending on the severity of the oxidative stress 25 , 26 , This extensive crosstalk occurs in multiple ways, and has been reviewed elsewhere 32 , 33 , 34 , 35 , Shown are many potential antioxidant and pro-oxidant targets that have been proposed in the literature.

MnSOD is a mitochondrial enzyme that protects cells from oxidative stress by converting. Mice lacking MnSOD die perinatally after birth due to massive oxidative stress It is down-regulated in many oxidative diseases 42 , and may be up-regulated in some cancers It catalyzes a similar reaction, causing the dismutation of. SOD1-deficient mice have a shortened life span, have persistent oxidative damage and develop hepatocellular carcinoma An iron storage protein, FHC does not directly scavenge ROS, but protects the cell from oxidative damage by preventing iron-mediated generation of highly reactive.

OH radicals from H 2 O 2 Fenton reaction. OH and promoting the breakdown of H 2 O 2 into water by peroxidases and catalases Thioredoxins protect from oxidative stress by means of their 2-cysteine active site that reacts with ROS and is also able to reduce oxidized proteins. They also serve as hydrogen donors to the thioredoxin-dependent peroxide reductases.

Trx1 is expressed in the cytoplasm and nucleus. Inactivation of Trx1 in mice also results in early embryonic lethality Trx2 is localized within the mitochondria and is also indispensable for cell survival 51 , Deletion of Trx2 causes massive apoptosis due to the accumulation of intracellular ROS, resulting in early embryonic lethality in homozygous mice GST-pi is a phase II enzyme that catalyzes the reaction of the GSH thiolate to toxic electrophilic compounds, thus allowing highly reactive carcinogens or radicals to be eliminated by excretion machinery 54 , It also is proposed to contribute to the repair of damage from oxidative stress.

Metallothioneins are low-molecular-weight, cysteine-rich proteins which bind to many different metals In addition to regulating metal toxicity, the cysteine residues in metallothioneins can scavenge. OH radicals This FAD-binding protein is a cytoplasmic 2-electron reductase that reduces quinones to hydroquinones. Since it is a 2-electron reductase, its enzymatic activity prevents the one electron reduction of quinones that produces radical species Heme oxygenase-1 catalyzes heme degradation, resulting in the formation of carbon monoxide and biliverdin, which is subsequently reduced to bilirubin by biliverdin reductase Since bilirubin is a potent antioxidant, it is thought that HO-1 is therefore protective from oxidative stress.

Glutathione peroxidase-1 Gpx1 is an abundant cytoplasmic enzyme that catalyzes the conversion of H 2 O 2 into water using glutathione as a substrate It is one of the most important members of antioxidant proteins.

Although it prefers H 2 O 2 as a substrate, it also can reduce lipid peroxides 67 , as well as peroxynitrite DDH1 is a phase-2 aldoketo reductase and oxidizes transdihydrodiols of polycyclic aromatic hydrocarbons. Like many phase-2 enzymes that activate toxic compounds to eliminate them from the body, the reactive products downstream of its reaction have been associated with induction of ROS Below, we discuss a few involved in the generation of ROS.

The dehydrogenase form is the most dominant form in vivo , however it may be converted to the oxidase form through the oxidation of its protein sulphydryl groups ROS production from XOR is implicated in several pathological conditions, including heart failure While technically nitric oxide synthases actually produce a reactive nitrogen species i. Peroxynitrite can cause various kinds of cellular damage, including damage to DNA, and can activate cell death pathways At low levels, peroxynitrite, and its resultant radicals may participate in signal transduction pathways, in a large part by tyrosine nitration Thus the expression of nitric oxide synthases can potentiate ROS damage as well as signaling.

During the second step of the reaction that produces PGH 2 , superoxide is also generated Thus, superoxide is a side product of this reaction, and may contribute to oxidative stress as well as signaling. As with COXmediated reactions, oxidized metabolites and byproducts of these enzymatic reactions contribute to ROS within the cell 89 , Cytochrome p enzymes , which are phase I enzymes that detoxify toxic compounds, have long been known to produce ROS when uncoupled, particularly H 2 O 2 and hydroxyl radicals 92 , 93 , 94 , While many of the differences noted in the literature are probably due to the use of different methodology, many of the differences are also attributed to the study of different upstream pathways and cell-specific differences.

Many of these interactions occur in a cell type-specific manner. ROS has been proposed to both activate and inactivate the IKK complex leading to an effect on the downstream targets.

Oxidation of p50 on its DNA binding domain has been shown to prevent its DNA binding, and must be reversed in the nucleus by a Trx1-dependent process involving Ref The best characterized way in which ROS affects signaling is through its reaction with cysteine, especially at an enzyme's catalytic sites, where the cysteine has a low pKa and exists in the thiolate form A primary example is that of protein tyrosine phosphatases, which have been shown to be inactivated by ROS through oxidation of catalytic cysteines , , Saha, S.

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