Abstract

BackgroundSignaling networks in eukaryotes are made up of upstream and downstream subnetworks. The upstream subnetwork contains the intertwined network of signaling pathways, while the downstream regulatory part contains transcription factors and their binding sites on the DNA as well as microRNAs and their mRNA targets. Currently, most signaling and regulatory databases contain only a subsection of this network, making comprehensive analyses highly time-consuming and dependent on specific data handling expertise. The need for detailed mapping of signaling systems is also supported by the fact that several drug development failures were caused by undiscovered cross-talk or regulatory effects of drug targets. We previously created a uniformly curated signaling pathway resource, SignaLink, to facilitate the analysis of pathway cross-talks. Here, we present SignaLink 2, which significantly extends the coverage and applications of its predecessor.DescriptionWe developed a novel concept to integrate and utilize different subsections (i.e., layers) of the signaling network. The multi-layered (onion-like) database structure is made up of signaling pathways, their pathway regulators (e.g., scaffold and endocytotic proteins) and modifier enzymes (e.g., phosphatases, ubiquitin ligases), as well as transcriptional and post-transcriptional regulators of all of these components. The user-friendly website allows the interactive exploration of how each signaling protein is regulated. The customizable download page enables the analysis of any user-specified part of the signaling network. Compared to other signaling resources, distinctive features of SignaLink 2 are the following: 1) it involves experimental data not only from humans but from two invertebrate model organisms, C. elegans and D. melanogaster; 2) combines manual curation with large-scale datasets; 3) provides confidence scores for each interaction; 4) operates a customizable download page with multiple file formats (e.g., BioPAX, Cytoscape, SBML). Non-profit users can access SignaLink 2 free of charge at http://SignaLink.org.ConclusionsWith SignaLink 2 as a single resource, users can effectively analyze signaling pathways, scaffold proteins, modifier enzymes, transcription factors and miRNAs that are important in the regulation of signaling processes. This integrated resource allows the systems-level examination of how cross-talks and signaling flow are regulated, as well as provide data for cross-species comparisons and drug discovery analyses.

Highlights

  • Signaling networks in eukaryotes are made up of upstream and downstream subnetworks

  • With SignaLink 2 as a single resource, users can effectively analyze signaling pathways, scaffold proteins, modifier enzymes, transcription factors and miRNAs that are important in the regulation of signaling processes

  • We added two further extensions that can be optionally used. i) With manual curation, we collected scaffold proteins and endocytosis-related proteins and linked them to signaling pathway proteins, based on the scaffold protein list of the Ref. [13] and signaling-related endocytosis reviews, respectively. ii) We extended the number of transcription factors (TFs) in the database from 243 to 586 by connecting additional TFs to already curated TFs, based on protein-protein interaction (PPI) data from WI8, DroID, HPRD and BioGRID databases [14,15,16,17]

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Summary

Conclusions

We presented the upgraded and extended version of the SignaLink resource that allows users to explore signaling pathway interactions and to identify pathway regulators, as well as transcriptional and post-transcriptional regulatory components. With SignaLink 2 users can examine in a single resource how scaffolds, enzymes, TFs or miRNAs regulate cross-talks and signaling flow. We hope that SignaLink 2 will be an efficient resource for modeling signaling systems as well as for signaling-related network medicine and pharmacology. DF, DT, DM and MSB integrated the external resources and constructed the SignaLink 2 database. DT developed the website, DF wrote the download module. LZ, KL, FIJ and TK participated in the design of the database and website. FIJ, TV, PC and TK wrote the manuscript. All authors read and approved the final manuscript

Background
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62. Wishart DS
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