Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery

Korcsmáros, Tamás; Farkas, Illés J.; Szalay, Máté; Rovó, Petra; Fazekas, Dávid; Spiró, Zoltán; Böde, Csaba; Lenti, Katalin; Vellai, Tibor; Csermely, Péter

doi:10.1093/bioinformatics/btq310

Cited by 69 publications

(101 citation statements)

References 113 publications

(129 reference statements)

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“…For the manual curation of the NRF2 interactome, we applied a curation protocol which is similar to the one that we have previously developed for the manual curation of 8 major signaling pathways in 3 organisms [14]. To identify additional interactors for NRF2, we predicted protein-protein interactions based on possible domain-domain and domain-motifs interactions.…”

Section: Building the Nrf2 Interactome And Regulomementioning

confidence: 99%

“…While there are more than 2300 articles for the keyword 'NRF2' in PubMed (as of January 2012), major protein-protein interaction resources (BioGRID, MINT, STRING, HPRD) contain only a few (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) interactors for NRF2. Besides one study on the global mapping of binding sites for NRF2 through ChIP-Seq profiling [10] and a specific network modeling approach on Nrf2 regulation in mouse lung [11], there is no large-scale collection of NRF2-regulated target genes.…”

Section: Introductionmentioning

confidence: 99%

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The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

et al. 2012

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a b s t r a c t NRF2 is a well-known, master transcription factor (TF) of oxidative and xenobiotic stress responses. Recent studies uncovered an even wider regulatory role of NRF2 influencing carcinogenesis, inflammation and neurodegeneration. Prompted by these advances here we present a systems-level resource for NRF2 interactome and regulome that includes 289 protein-protein, 7469 TF-DNA and 85 miRNA interactions. As systems-level examples of NRF2-related signaling we identified regulatory loops of NRF2 interacting proteins (e.g., JNK1 and CBP) and a fine-tuned regulatory system, where 35 TFs regulated by NRF2 influence 63 miRNAs that down-regulate NRF2. The presented network and the uncovered regulatory loops may facilitate the development of efficient, NRF2-based therapeutic agents.

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Section: Building the Nrf2 Interactome And Regulomementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

et al. 2012

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“…1 Manual curation process of SignaLink. To compile the SignaLink pathway resource [12] (http:/ /signalink.org), signaling interactions were collected from pathway reviews, species-specific databases, and UniProt. Only interactions with references were included after manual checks via PubMed.…”

Section: Compilation Of Signalinkmentioning

confidence: 99%

“…A comprehensive pathway resource, SignaLink, developed in our lab, applies uniform curation rules to keep the levels of detail identical in all examined pathways for Caenorhabditis elegans, Drosophila melanogaster, and humans [12]. Compared to three widely used pathway databases (KEGG, Reactome and NetPath), SignaLink contains the (1) highest numbers of signaling proteins and interactions; (2) highest numbers of signaling cross-talks and multi-pathway proteins; (3) and above the average number of publications used per pathway [12].…”

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confidence: 99%

“…Compared to three widely used pathway databases (KEGG, Reactome and NetPath), SignaLink contains the (1) highest numbers of signaling proteins and interactions; (2) highest numbers of signaling cross-talks and multi-pathway proteins; (3) and above the average number of publications used per pathway [12]. Moreover, the uniform curation protocol and data structure of the SignaLink database allow systematic transfer of pathway annotation between two species on the basis of sequence orthology.…”

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confidence: 99%

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Uniform Curation Protocol of Metazoan Signaling Pathways to Predict Novel Signaling Components

Pálfy

Farkas

Vellai

et al. 2013

Methods in Molecular Biology

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A relatively large number of signaling databases available today have strongly contributed to our understanding of signaling pathway properties. However, pathway comparisons both within and across databases are currently severely hampered by the large variety of data sources and the different levels of detail of their information content (on proteins and interactions). In this chapter, we present a protocol for a uniform curation method of signaling pathways, which intends to overcome this insufficiency. This uniformly curated database called SignaLink (http://signalink.org) allows us to systematically transfer pathway annotations between different species, based on orthology, and thereby to predict novel signaling pathway components. Thus, this method enables the compilation of a comprehensive signaling map of a given species and identification of new potential drug targets in humans.We strongly believe that the strict curation protocol we have established to compile a signaling pathway database can also be applied for the compilation of other (e.g., metabolic) databases. Similarly, the detailed guide to the orthology-based prediction of novel signaling components across species may also be utilized for predicting components of other biological processes.

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Analysis of pathway mutation profiles highlights collaboration between cancer-associated superpathways

Zhao

Xia

et al. 2011

Hum. Mutat.

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The biological interpretation of the complexity of cancer somatic mutation profiles is a major challenge in current cancer research. It has been suggested that mutations in multiple genes that participate in different pathways are collaborative in conferring growth advantage to tumor cells. Here, we propose a powerful pathway-based approach to study the functional collaboration of gene mutations in carcinogenesis. We successfully identify many pairs of significantly comutated pathways for a large-scale somatic mutation profile of lung adenocarcinoma. We find that the coordinated pathway pairs detected by comutations are also likely to be coaltered by other molecular changes, such as alterations in multifunctional genes in cancer. Then, we cluster comutated pathways into comutated superpathways and show that the derived superpathways also tend to be significantly coaltered by DNA copy number alterations. Our results support the hypothesis that comprehensive cooperation among a few basic functions is required for inducing cancer. The results also suggest biologically plausible models for understanding the heterogeneous mechanisms of cancers. Finally, we suggest an approach to identify candidate cancer genes from the derived comutated pathways. Together, our results provide guidelines to distill the pathway collaboration in carcinogenesis from the complexity of cancer somatic mutation profiles.

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Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery

Abstract: http://SignaLink.org.

Cited by 69 publications

References 113 publications

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

The NRF2‐related interactome and regulome contain multifunctional proteins and fine‐tuned autoregulatory loops

Uniform Curation Protocol of Metazoan Signaling Pathways to Predict Novel Signaling Components

Analysis of pathway mutation profiles highlights collaboration between cancer-associated superpathways

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