Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 113, Issue 18, Pages 4976-4981Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1603992113
Keywords
network biology; controllability; protein-protein interaction network; disease genes; drug targets
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Funding
- National Institutes of Health (NIH) [P01-CA120964]
- Centers of Excellence of Genomic Science (CEGS) [1P50HG004233, 1R01HL118455-01A1]
- John Templeton Foundation [PFI-777, 51977]
- Howard Hughes Medical Institute
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The protein-protein interaction (PPI) network is crucial for cellular information processing and decision-making. With suitable inputs, PPI networks drive the cells to diverse functional outcomes such as cell proliferation or cell death. Here, we characterize the structural controllability of a large directed human PPI network comprising 6,339 proteins and 34,813 interactions. This network allows us to classify proteins as indispensable, neutral, or dispensable, which correlates to increasing, no effect, or decreasing the number of driver nodes in the network upon removal of that protein. We find that 21% of the proteins in the PPI network are indispensable. Interestingly, these indispensable proteins are the primary targets of disease-causing mutations, human viruses, and drugs, suggesting that altering a network's control property is critical for the transition between healthy and disease states. Furthermore, analyzing copy number alterations data from 1,547 cancer patients reveals that 56 genes that are frequently amplified or deleted in nine different cancers are indispensable. Among the 56 genes, 46 of them have not been previously associated with cancer. This suggests that controllability analysis is very useful in identifying novel disease genes and potential drug targets.
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