SignaLink 2 - a signaling pathway resource with multi-layered regulatory networks.

BACKGROUND Signaling 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. DESCRIPTION We 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. CONCLUSIONS 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. 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

SignaLink 2 - a signaling pathway resource with multi-layered regulatory networks

ABSTRACT: BACKGROUND: Signaling 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.Description: We 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 CONCLUSIONS: 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. 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

ModuLand plug-in for Cytoscape: determination of hierarchical layers of overlapping network modules and community centrality

Summary: The ModuLand plug-in provides Cytoscape users an algorithm for determining extensively overlapping network modules. Moreover, it identifies several hierarchical layers of modules, where meta-nodes of the higher hierarchical layer represent modules of the lower layer. The tool assigns module cores, which predict the function of the whole module, and determines key nodes bridging two or multiple modules. The plug-in has a detailed JAVA-based graphical interface with various colouring options. The ModuLand tool can run on Windows, Linux, or Mac OS. We demonstrate its use on protein structure and metabolic networks. Availability: The plug-in and its user guide can be downloaded freely from: http://www.linkgroup.hu/modules.php. Contact: [email protected] Supplementary information: Supplementary information is available at Bioinformatics online.Comment: 39 pages, 1 figure and a Supplement with 9 figures and 10 table

The EntOptLayout Cytoscape plug-in for the efficient visualization of major protein complexes in protein-protein interaction and signalling networks

Motivation: Network visualizations of complex biological datasets usually result in 'hairball' images, which do not discriminate network modules. Results: We present the EntOptLayout Cytoscape plug-in based on a recently developed network representation theory. The plug-in provides an efficient visualization of network modules, which represent major protein complexes in protein-protein interaction and signalling networks. Importantly, the tool gives a quality score of the network visualization by calculating the information loss between the input data and the visual representation showing a 3- to 25-fold improvement over conventional methods. Availability: The plug-in (running on Windows, Linux, or Mac OS) and its tutorial (both in written and video forms) can be downloaded freely under the terms of the MIT license from: http://apps.cytoscape.org/apps/entoptlayout. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Biológiai hálózatok átfedő modularizálását végző számítógépes programok és azok alkalmazási területei

A disszertációmban bemutatott tudományos munkám célja, hogy a bonyolult biológiai rendszerek megértését segítsem elő olyan informatikai programok fejlesztésével, amelyek segítenek az élő rendszereket leíró hálózatos modellek szerkezetének feltérképezésében. A dolgozatomban a ModuLand nevű fuzzy modularizálási eljárás informatikai megvalósítását és az eljárás gyakorlati példákon való alkalmazását ismertetem. Az általam megvalósított program segítségével vizsgálhatóvá válik tetszőleges irányítatlan hálózat hierarchikus modulszerkezete. A program képes a modulok központi régióinak meghatározására, valamint a hálózat egyes pontjainak a modulszerkezetben betöltött szerepének számszerű jellemzésére. Például egy fehérje-fehérje kölcsönhatási hálózat esetén megállapítható, hogy az adott fehérje mennyire játszik központi szerepet egy funkcionális modulban, vagy épp mennyire alkot hidat különböző funkcionális modulok között. Az általam fejlesztett plug-in-t számos biológiai kutatás során felhasználtam részben én, részben a kutatócsoportom tagjai és részben más nemzetközi kutatócsoportok. Az Escherichia coli baktéirium Met-tRNS szintetáz fehérjéjének térszerkezetét modellező aminosav hálózat esetében összevetettem a hálózat modulszerkezetét a fehérje domain szerkezetével, illetve megvizsgáltam az enzim katalitikus központja és antikodon kötőhelye közötti konformációs változások továbbadásáért felelős aminosavak modulszerkezetben betöltött pozícióját és ezek sajátosságait. A ModuLand plug-in használatával munkatársaimmal közösen összehasonlítottuk a Buchnera Aphidicola és Escherichia coli baktériumok metabolikus folyamatait leíró hálózatokat, kimutatva az előbbi élőlénynél a szabadon élő, illetve az utóbbi esetében a szimbióta életmódból fakadó különbségeket a metabolikus hálók modulszerkezeteiben. Az általam megvalósított ModuLand plug-in-t 2012-es publikálása óta több mint 150 kutató töltötte le és több nemzetközi publikációban közölt, tőlem független kutatásnál felhasználásra került