The Network Biology (NetBiol) Group is at the Department of Genetics of the Eötvös Loránd University. The NetBiol Group works in close cooperation with the LINK-Group led by Prof. Peter Csermely and with the experimental C. elegans lab led by Tibor Vellai. Our completed research projects include (1) the development of a signaling pathway database, which focuses especially on signaling cross-talk and regulatory mechanisms to control signaling flow, (2) the identification of novel signalling proteins, (3) the development of the PathwayLinker webservice that analyzes the signaling pathway memberships of proteins as well as their interactors for experiment design and evaluation, (4) a systems-level resource about the interaction and regulatory network of NRF2, a major transcription factor important in antioxidant response and cancer therapy.
Currently, we are focusing on the systems-level analysis of the signaling flow and the processes that regulate signaling pathways. We are examining the connection between the networks of signaling and autophagy, a cellular degradative process, which affects aging and tumorgenesis.
The induction of autophagy is quite uniform and well studied in Unikonts (e.g. yeast, animals and Dictyostelium): autophagy is induced by the activation of the ATG1/ULK1-complex. We performed an extensive bioinformatics analysis within non-unikont parasites (e.g. Trypanosoma, Leishmania, Toxoplasma). Based on our results we show that non-unikont parasites lack the ATG1/ULK1-complex. Thus, in these parasites, autophagy could only be induced in a different way that is known in Unikonts. These fundamental differences between human and parasites may have important therapeutic applications. See also a more detailed Press Release and a Blog post. The article can be downloaded from HERE.
Tamas Korcsmaros has been appointed as a Computational Fellow at TGAC, The Genome Analysis Centre (Norwich, UK).
Tamas Korcsmaros, the PI of the NetBiol Group will move his base to Norwich in Spring 2014 to work in the TGAC institute as a computational biology fellow. This appointment is for 5 years, in close collaboration with the Institute of Food Research. Tamas will work on the regulation of human autophagy by foodborne pathogens and probiotics with computational and wet lab approaches. The NetBiol Team will be led by David Fazekas, a senior member of the group for many years. For further information, please see the following Press Release.
A cancer-related network issue of Seminars in Cancer Biology contains two reviews written in collaboration with the LINK-group. In Kubisch et al., we present integrated approaches to investigate the double-edged sword effect of autophagy in cancer by focusing on the autophagy regulatory network. In Gyurko et al., we describe the hallmarks of increased system plasticity of early, tumor initiating cells, and argue that the large structural changes of molecular networks during cancer development necessitate a rather different targeting strategy in early and in late phase of carcinogenesis.
Tamas Korcsmaros became an editor of (Nature) Scientific Reports. Scientific Reports is a primary research publication from the publishers of Nature, covering all areas of the natural sciences. Scientific Reports is open to all, publishing technically sound, original research papers of interest to specialists within their field, without barriers to access.
Our comprehensive review on the use of networks in drug design published recently in Pharmacology & Therapeutics was recommended two times as an F1000 Prime paper by Mark Ragan and Vladimir Uversky. Both recommendations gave the maximum 3-star level for our paper. In this review we provided a summary of current methods assessing network topology and dynamics and gave extensive examples on their use in drug design. We have formulated several novel concepts (such as network identification of multi-target and allo-network drugs, optimized protocol of network-aided drug development, etc.), which will potentially help the progress in this field.
Diana Papp received the prestigious BioScience Award at the Hungarian Molecular Life Sciences Conference. This award is presented each year to the first author of an outstanding paper appeared in the preceding year. Diana received this award for her paper in PLoS Pathogens, where she showed the role of SKN-1/Nrf2 in the pathogen resistance of C. elegans. Zoltan Dúl and Dezső Módos received a Commendatory place at the National Conference of University Research Students (OTDK) for their three years research work on the analysis of network motifs in cellular signaling systems. Zsuzsanna Dunai successfully defended her PhD thesis on programmed cell death.
A summary paper on the teaching methodology of signaling networks appeared in Briefings in Bioinformatics
As part of a special education issue, we described how signaling network offers an excellent example for teaching bioinformatics resources and tools. We presented an outline of a university bioinformatics course with four sample practices to demonstrate how signaling network studies can integrate biochemistry, genetics, cell biology, and network sciences. The research-type hands-on experiences we showed enable the students to improve key competences such as team-working, creative and critical thinking and problem-solving. The paper can be accessed HERE.
We have developed a novel network resource to provide an integrated database for NRF2 researchers. NRF2-ome contains manually curated and predicted interactions of NRF2 as well as data from external interaction databases. We connected NRF2-ome to signaling pathways to allow mapping upstream NRF2 regulatory components. The user-friendly website allows researchers without computational background to search, browse and download the database in SQL, CSV, BioPAX, SBML, PSI-MI and in a Cytoscape CYS file formats. The paper appeared in a special issue of Oxidative Medicine and Cellular Longevity describing the novel resource can be found HERE, while the website can be accessed from http://nrf2.elte.hu.
The March 5th 2013 issue of Science Signaling highlighted the SignaLink database as a new bioinformatics resource in its ST NetWatch section. SignaLink has been published recently in BMC Systems Biology and earlier in Bioinformatics and provides a multi-layered database of signaling pathways and their regulators.
Our comprehensive review on the use of networks in drug design was published in Pharmacology & Therapeutics
In the review we cited 1270 references, and gave extensive examples on the use of network approach in drug design. Several novel concepts were formulated, including the concept of the "central hit strategy", which selectively targets central node/edges of the flexible networks of infectious agents or cancer cells to kill them. On the contrary, the "network influence strategy" works against other diseases, where an efficient reconfiguration of rigid networks needs to be achieved. The review can be downloaded from HERE.
We developed a novel concept to integrate and utilize different subsections 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. The paper describing SignaLink 2 can be accessed HERE.
With a bioinformatics analysis we identified 12 novel signatures for cancer associated fibroblasts. The paper published in the International Journal of Cancer describes the method, the genes and their network. The paper can be downloaded from HERE.
Tamás Korcsmáros has received the prestigeous Prima Junior Award recognizing excellent Hungarian young scientists. This award is given annually for 10 outstanding young scientists each year (usually one biologist).
An interview in Hungarian with Tamás Korcsmáros can be found here.
For more information about the prize click here (in Hungarian).
Our Opinion article was #1 most read article in Trends in Cell Biology for 6 weeks and was among the top10 downloads for 3 months
The list of most read articles of Trends in Cell Biology shows our opinion article on endosomal cross-talk as one of the most downloaded papers. In this paper we described that cross-talk endosomes and endosome-associated scaffold proteins could precisely mediate the interaction of different pathway components.
Endosomes could serve as physical platforms for cross-talk between signaling pathways. ‘Cross-talk endosomes’, as meeting points for signaling pathways, are capable to maintain the specificity, signal strength and localization of inter-pathway communication. We suggest that cross-talk endosomes and endosome-associated scaffold proteins may be principle components to precisely mediate the interaction of different pathway components. Our Opinion article can be downloaded from HERE, while accompanying datasets is available from HERE.
Tamas Korcsmaros received the János Bolyai Research Scholarship from the Hungarian Academy of Sciences. László Földvári-Nagy successfully defended his Master thesis on the examination of autophagy induction in Protist species, and received an M.Sc. degree. Dezső Módos received his MD degree after successfully passing the final exam at the Semmelweis University. Bálint Őry defended his BA thesis on the cognitive processes of molecular and organ-level systems, and received a B.Sc. degree. Katalin Lenti has been appointed as an assistant professor of the Semmelweis University.
We have created the interactome and regulome of NRF2 a master transcription factor of oxidative and xenobiotic stress responses. NRF2 is known to have roles in carcinogenesis, inflammation and neurodegeneration. We present a systems-level resource for NRF2 that includes 289 protein-protein, 7469 TF-DNA and 85 miRNA interactions – based on manual curation, in silico prediction and existing dataset imports. We identified regulatory loops of NRF2 interacting proteins and a fine-tuned regulatory system, where 35 TFs regulated by NRF2 influence 63 miRNAs that down-regulate NRF2. The paper can be downloaded from HERE, while the accompanying dataset is available from HERE.
Article on the role of SKN-1/NRF2 in pathogen resistance and immunosenescence of C. elegans has been published in PLoS Pathogens
The C. elegans transcription factor SKN-1 C. elegans pathogen resistance. This paper describes that the SKN-1-dependent response to pathogen exposure declines during aging, whereas mild metabolic and oxidative stresses, known to extend lifespan, evoke a SKN-1-dependent boosting of immunity.
The paper can be downloaded from here.
Biomedical experimental work often focuses on altering the functions of selected proteins. These changes can hit signaling pathways, and can therefore unexpectedly and non-specifically affect cellular processes. We developed PathwayLinker, an online tool that can provide a first estimate of the possible signaling effects of such changes, e.g., drug or microRNA treatments.The article describing the workflow of PathwayLinker with several examples can be downloaded from here.
A summary paper of our results appeared in Science Signaling: Network-based tools in the identification of novel drug-targets
A summary paper and an accompanying slide show of our work appeared in the May 2011 issue of Science Signaling. Slides were updated from the opening presentation at the International Conference on Systems Biology of Human Disease (SBHD) in Boston, Massachusetts, 16 to 18 June 2010. The paper contains several novel ideas on network dynamics and drug design, a summary of our very recent results as well as a brief description of a few ongoing projects.
In connection with the SignaLink database, we published the concept of signaling orthologs, called signalogs in PLoS ONE. The paper (which also contains and experimental "proof-of-concept" on the predicting power of SignaLink) can be downloaded from here. To identify signalogs on genomic scale, we systematically transferred signaling pathway annotations among three animal species, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and humans. We predicted 88 worm, 92 fly, and 73 human novel signaling components. Furthermore, we developed an on-line tool and an interactive orthology network viewer to allow users to predict and visualize components of orthologous pathways. Our approach predicts signaling roles for 19 human orthodisease proteins and 5 known drug targets, and suggests 14 novel drug target candidates.
SignaLink is a uniformly curated signaling pathway resource for cross-talk analysis of Caenorhabditis elegans, Drosophila melanogaster and Homo sapiens.
Analyses of a uniformly curated signaling pathway database of the 3 metazoans revealed novel pathway components, drug target candidates, and produced a large-scale view of the cross-talk network of pathways where tissue-specific cross-talk utilization was discovered.
Supporting website can be found here.
Link to the Bioinformatics article can be found here.