Bioinformatics Knowledge Map for Analysis of Beta-Catenin Function in Cancer
Date
2015-10-28
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Publisher
Public Library of Science
Abstract
Given the wealth of bioinformatics resources and the growing complexity of biological information,
it is valuable to integrate data from disparate sources to gain insight into the role of
genes/proteins in health and disease. We have developed a bioinformatics framework that
combines literature mining with information from biomedical ontologies and curated databases
to create knowledge “maps” of genes/proteins of interest.We applied this approach
to the study of beta-catenin, a cell adhesion molecule and transcriptional regulator implicated
in cancer. The knowledge map includes post-translational modifications (PTMs), protein-
protein interactions, disease-associated mutations, and transcription factors coactivated
by beta-catenin and their targets and captures the major processes in which betacatenin
is known to participate. Using the map, we generated testable hypotheses about
beta-catenin biology in normal and cancer cells. By focusing on proteins participating in multiple
relation types, we identified proteins that may participate in feedback loops regulating
beta-catenin transcriptional activity. By combining multiple network relations with PTM proteoform-
specific functional information, we proposed a mechanism to explain the observation
that the cyclin dependent kinase CDK5 positively regulates beta-catenin co-activator
activity. Finally, by overlaying cancer-associated mutation data with sequence features, we
observed mutation patterns in several beta-catenin PTM sites and PTM enzyme binding
sites that varied by tissue type, suggesting multiple mechanisms by which beta-catenin
mutations can contribute to cancer. The approach described, which captures rich information
for molecular species from genes and proteins to PTM proteoforms, is extensible to
other proteins and their involvement in disease.
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Citation
Çelen İ, Ross KE, Arighi CN, Wu CH (2015) Bioinformatics Knowledge Map for Analysis of Beta- Catenin Function in Cancer. PLoS ONE 10(10): e0141773. doi:10.1371/journal.pone.0141773