Benchmarking of protein interaction databases for integration with manually reconstructed signaling network models.

Protein interaction databases are critical resources for network bioinformatics and integrating molecular experimental data. Interaction databases may also enable construction of predictive computational models of biological networks, although their fidelity for this purpose is not clear. Here, we benchmark protein interaction databases X2K, Reactome, Pathway Commons, Omnipath, and Signor for their ability to recover manually curated edges from three logic-based network models of cardiac hypertrophy, mechano-signaling, and fibrosis. Pathway Commons performed best at recovering interactions from manually reconstructed hypertrophy (137 of 193 interactions, 71%), mechano-signaling (85 of 125 interactions, 68%), and fibroblast networks (98 of 142 interactions, 69%). While protein interaction databases successfully recovered central, well-conserved pathways, they performed worse at recovering tissue-specific and transcriptional regulation. This highlights a knowledge gap where manual curation is critical. Finally, we tested the ability of Signor and Pathway Commons to identify new edges that improve model predictions, revealing important roles of PKC autophosphorylation and CaMKII phosphorylation of CREB in cardiomyocyte hypertrophy. This study provides a platform for benchmarking protein interaction databases for their utility in network model construction, as well as providing new insights into cardiac hypertrophy signaling. KEY POINTS: Protein interaction databases are used to recover signaling interactions from previously developed network models. The 5 protein interaction databases benchmarked recovered well-conserved pathways, but did poorly at recovering tissue-specific pathways and transcriptional regulation, indicating the importance of manual curation. We identify new signaling interactions not previously used in the network models, including a role for CaMKII phosphorylation of CREB in cardiomyocyte hypertrophy. Abstract figure legend Process used to benchmark protein interaction databases against manually curated network models. Manual network reconstructions were translated into a tabular format that matched files obtained from protein interaction databases. This article is protected by copyright. All rights reserved.