Abstract
A major objective of systems biology is to organize molecular interactions as networks and to characterize information flow within networks. We describe a computational framework to integrate protein-protein interaction (PPI) networks and genetic screens to predict the 'signs' of interactions (i.e., activation-inhibition relationships). We constructed a Drosophila melanogaster signed PPI network consisting of 6,125 signed PPIs connecting 3,352 proteins that can be used to identify positive and negative regulators of signaling pathways and protein complexes. We identified an unexpected role for the metabolic enzymes enolase and aldo-keto reductase as positive and negative regulators of proteolysis, respectively. Characterization of the activation-inhibition relationships between physically interacting proteins within signaling pathways will affect our understanding of many biological functions, including signal transduction and mechanisms of disease.
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Change history
17 March 2014
In the version of this article initially published, there was an error in the expression describing the sign score Ssign. The variable Tn in the denominator should have been Tp. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
We thank B. Housden, Y. Kwon, I.T. Flockhart and S. Rajagopal for helpful suggestions for tool development and manuscript preparation. This work was financially supported by P01-CA120964, R01-GM067761 and R01DK088718. S.E.M. is also supported in part by the Dana-Farber/Harvard Cancer Center (P30-CA06516). N.P. is supported by the Howard Hughes Medical Institute.
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Contributions
A.V. and N.P. conceived of and designed the project. A.V. developed the computational method and built and analyzed the signed network. J.Z. designed and performed experimental validation. C.R. and B.Y. developed the SignedPPI database. A.V. and S.E.M. coordinated the development of the SignedPPI database. A.V. and Y.H. compiled RNAi screens. A.A.S. analyzed modENCODE expression data. R.A.N. contributed the unpublished RNAi screen. All authors contributed to manuscript preparation.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–11, Supplementary Tables 1–6, 8, 9 and 11–14 (PDF 3922 kb)
Supplementary Table 7
Signed PPI network integrated with gene-expression datasets from modENCODE database (XLSX 799 kb)
Supplementary Table 10
List of triad motifs extracted from the signed network (XLSX 184 kb)
Supplementary Table 15
Signed functional interaction network constructed based on STRING interactions. Only STRING interactions with confidence score ≥ 700 is considered for the analysis (XLSX 2275 kb)
Supplementary Data
Images correspond to RNAi screen in Drosophila primary embryonic muscle cells. Each image corresponds to a single gene and a single field out of 24 fields per well. Individual image files are named as follows, gene names followed by the amplicon ID (ZIP 84492 kb)
Supplementary Software
SignPredictor tool to predict signed PPIs. (ZIP 591 kb)
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Vinayagam, A., Zirin, J., Roesel, C. et al. Integrating protein-protein interaction networks with phenotypes reveals signs of interactions. Nat Methods 11, 94–99 (2014). https://doi.org/10.1038/nmeth.2733
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DOI: https://doi.org/10.1038/nmeth.2733
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