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The human kinome is gaining importance through its promising cancer therapeutic targets, yet no general model to address the kinase inhibitor resistance has emerged. Here, we constructed a systems biology-based framework to catalogue the human kinome, including 538 kinase genes, in the broader context of the human interactome. Specifically, we constructed three networks: a kinase-substrate interaction network containing 7,346 pairs connecting 379 kinases to 36,576 phosphorylation sites in 1,961 substrates, a protein-protein interaction network (PPIN) containing 92,699 pairs, and an atomic resolution PPIN containing 4,278 pairs. We identified the conserved regulatory phosphorylation motifs (e.g., Ser/Thr-Pro) using a sequence logo analysis. We found the typical anticancer target selection strategy that uses network hubs as drug targets, might lead to a high adverse drug reaction risk. Furthermore, we found the distinct network centrality of kinases creates a high anticancer drug resistance risk by feedback or crosstalk mechanisms within cellular networks. This notion is supported by the systematic network and pathway analyses that anticancer drug resistance genes are significantly enriched as hubs and heavily participate in multiple signaling pathways. Collectively, this comprehensive human kinome interactome map sheds light on anticancer drug resistance mechanisms and provides an innovative resource for rational kinase inhibitor design.
Pubmed ID: 25003367
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A user-sponsored molecular visualization software system on an open-source foundation. The software has the capabilities to view, render, animate, export, present and develop three dimensional molecular structures.
View all literature mentionsSoftware environment and programming language for statistical computing and graphics. R is integrated suite of software facilities for data manipulation, calculation and graphical display. Can be extended via packages. Some packages are supplied with the R distribution and more are available through CRAN family.It compiles and runs on wide variety of UNIX platforms, Windows and MacOS.
View all literature mentionsDatabase of human genes that provides concise genomic, proteomic, transcriptomic, genetic and functional information on all known and predicted human genes. Information featured in GeneCards includes orthologies, disease relationships, mutations and SNPs, gene expression, gene function, pathways, protein-protein interactions, related drugs and compounds and direct links to cutting edge research reagents and tools such as antibodies, recombinant proteins, clones, expression assays and RNAi reagents.
View all literature mentionsA genomics database project is an academic research program to identify molecular features of cancers that predict response to anti-cancer drugs.
View all literature mentionsCollection of structural data of biological macromolecules. Database of information about 3D structures of large biological molecules, including proteins and nucleic acids. Users can perform queries on data and analyze and visualize results.
View all literature mentionsOpen source database system and analysis tools for molecular interaction data. All interactions are derived from literature curation or direct user submissions. Direct user submissions of molecular interaction data are encouraged, which may be deposited prior to publication in a peer-reviewed journal. The IntAct Database contains (Jun. 2014): * 447368 Interactions * 33021 experiments * 12698 publications * 82745 Interactors IntAct provides a two-tiered view of the interaction data. The search interface allows the user to iteratively develop complex queries, exploiting the detailed annotation with hierarchical controlled vocabularies. Results are provided at any stage in a simplified, tabular view. Specialized views then allows "zooming in" on the full annotation of interactions, interactors and their properties. IntAct source code and data are freely available.
View all literature mentionsA database that focuses on experimentally verified protein-protein interactions mined from the scientific literature by expert curators. The curated data can be analyzed in the context of the high throughput data and viewed graphically with the MINT Viewer. This collection of molecular interaction databases can be used to search for, analyze and graphically display molecular interaction networks and pathways from a wide variety of species. MINT is comprised of separate database components. HomoMINT, is an inferred human protein interatction database. Domino, is database of domain peptide interactions. VirusMINT explores the interactions of viral proteins with human proteins. The MINT connect viewer allows you to enter a list of proteins (e.g. proteins in a pathway) to retrieve, display and download a network with all the interactions connecting them.
View all literature mentionsDatabase that represents a centralized platform to visually depict and integrate information pertaining to domain architecture, post-translational modifications, interaction networks and disease association for each protein in the human proteome. All the information in HPRD has been manually extracted from the literature by expert biologists who read, interpret and analyze the published data.
View all literature mentionsCurated protein-protein and genetic interaction repository of raw protein and genetic interactions from major model organism species, with data compiled through comprehensive curation efforts.
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