title: Characterizing protein interactions employing a genome-wide siRNA cellular phenotyping screen.
abstract: Characterizing the activating and inhibiting effect of protein-protein interactions (PPI) is fundamental to gain insight into the complex signaling system of a human cell. A plethora of methods has been suggested to infer PPI from data on a large scale, but none of them is able to characterize the effect of this interaction. Here, we present a novel computational development that employs mitotic phenotypes of a genome-wide RNAi knockdown screen and enables identifying the activating and inhibiting effects of PPIs. Exemplarily, we applied our technique to a knockdown screen of HeLa cells cultivated at standard conditions. Using a machine learning approach, we obtained high accuracy (82% AUC of the receiver operating characteristics) by cross-validation using 6,870 known activating and inhibiting PPIs as gold standard. We predicted de novo unknown activating and inhibiting effects for 1,954 PPIs in HeLa cells covering the ten major signaling pathways of the Kyoto Encyclopedia of Genes and Genomes, and made these predictions publicly available in a database. We finally demonstrate that the predicted effects can be used to cluster knockdown genes of similar biological processes in coherent subgroups. The characterization of the activating or inhibiting effect of individual PPIs opens up new perspectives for the interpretation of large datasets of PPIs and thus considerably increases the value of PPIs as an integrated resource for studying the detailed function of signaling pathways of the cellular system of interest.
authors.affiliation: Department of Mathematics, Faculty of Applied Science, King Mongkut's University of Technology North Bangkok, Bangsue, Bangkok, Thailand.
authors.forename: Apichat
authors.initials: A
authors.lastname: Suratanee
authors.affiliation: EMBL/CRG Systems Biology Research Unit, Center for Genomic Regulation, Barcelona, Spain.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Schaefer
authors.affiliation: Robert B. Russell, Cell Networks Protein Evolution, BioQuant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Betts
authors.affiliation: Network Modeling, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena, Jena, Germany; Department of Knowledge Engineering, Maastricht University, Maastricht, The Netherlands; Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Zita
authors.initials: Z
authors.lastname: Soons
authors.affiliation: Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Mannsperger
authors.affiliation: Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, BioQuant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Harder
authors.affiliation: Network Modeling, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Oswald
authors.affiliation: Department of Computer Science V, Institute of Computer Engineering, University of Mannheim, Mannheim, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Gipp
authors.affiliation: AG Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Ellen
authors.initials: E
authors.lastname: Ramminger
authors.affiliation: Department of Computer Science V, Institute of Computer Engineering, University of Mannheim, Mannheim, Germany.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Marcus
authors.affiliation: Department of Computer Science V, Institute of Computer Engineering, University of Mannheim, Mannheim, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Männer
authors.affiliation: Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, BioQuant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Rohr
authors.affiliation: AG Neuroproteomics, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Erich
authors.initials: E
authors.lastname: Wanker
authors.affiliation: Robert B. Russell, Cell Networks Protein Evolution, BioQuant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Russell
authors.affiliation: Computational Biology and Data Mining Group, Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Andrade-Navarro
authors.affiliation: Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany; Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, BioQuant, University of Heidelberg, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.affiliation: Network Modeling, Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute Jena, Jena, Germany; Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany; Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: König
mesh_terms: D016000:Cluster Analysis; D030562:Databases, Protein; D055785:Gene Knockdown Techniques; D023281:Genomics / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D010641:Phenotype; D060066:Protein Interaction Maps; D011506:Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism*; D012372:ROC Curve
chemical_list: D011506:Proteins; D034741:RNA, Small Interfering