E3Net: A System for Exploring E3-mediated Regulatory Networks of Cellular Functions

Abstract

Ubiquitin-protein ligase (E3) is a key enzyme targeting specific substrates in diverse cellular processes for ubiquitination and degradation. The existing findings of substrate specificity of E3 are, however, scattered over a number of resources, making it difficult to study them together with an integrative view. Here we present E3Net, a web-based system that provides a comprehensive collection of available E3-substrate specificities and a systematic framework for the analysis of E3-mediated regulatory networks of diverse cellular functions. Currently, E3Net contains 2201 E3s and 4896 substrates in 427 organisms and 1671 E3-substrate specific relations between 493 E3s and 1277 substrates in 42 organisms, extracted mainly from MEDLINE abstracts and UniProt comments with an automatic text mining method and additional manual inspection and partly from high throughput experiment data and public ubiquitination databases. The significant functions and pathways of the extracted E3-specific substrate groups were identified from a functional enrichment analysis with 12 functional category resources for molecular functions, protein families, protein complexes, pathways, cellular processes, cellular localization, and diseases. E3Net includes interactive analysis and navigation tools that make it possible to build an integrative view of E3-substrate networks and their correlated functions with graphical illustrations and summarized descriptions. As a result, E3Net provides a comprehensive resource of E3s, substrates, and their functional implications summarized from the regulatory network structures of E3-specific substrate groups and their correlated functions. This resource will facilitate further in-depth investigation of ubiquitination-dependent regulatory mechanisms. E3Net is freely available online at http://pnet.kaist.ac.kr/e3net. Molecular & Cellular Proteomics

Systematic analysis of alterations in the ubiquitin proteolysis system reveals its contribution to driver mutations in cancer

“…The list of proteins involved in ubiquitination (UBSs) and deubiquitination (DUBs) was manually created by integrating previous knowledge from UniProt 17 and E3NET 55 . The final list of proteins involved in ubiquitination included 977 identifiers of human proteins.…”

UUCD: a family-based database of ubiquitin and ubiquitin-like conjugation

“…Aberrances of ubiquitin and ubiquitin-like conjugation systems are highly implicated in a variety of diseases and cancers (7,10). In this regard, identification and classification of E1s, E2s, E3s and DUBs is fundamental for dissecting the molecular mechanisms and regulatory roles of the conjugation (4,8,9), analyzing the phylogenetic relations of enzymes (8,23), modeling E3-substrate networks (32) and providing potent candidates for drug design (11). Developing a comprehensive database with detailed annotation and classification information has emerged to be an urgent challenge.…”

Inference of Disease E3s from Integrated Functional Relation Network

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