Systems biology iteratively combines experimentation with mathematical modeling. However, limited mechanistic knowledge, conflicting hypotheses and scarce experimental data severely hamper the development of predictive mechanistic models in many areas of biology. Even under such high uncertainty, we show here that ensemble modeling, when combined with targeted experimental analysis, can unravel key operating principles in complex cellular pathways. For proof of concept, we develop a library of mechanistically alternative dynamic models for the highly conserved target-of-rapamycin (TOR) pathway of Saccharomyces cerevisiae. In contrast to the prevailing view of a de novo assembly of type 2A phosphatases (PP2As), our integrated computational and experimental analysis proposes a specificity factor, based on Tap42p-Tip41p, for PP2As as the key signaling mechanism that is quantitatively consistent with all available experimental data. Beyond revising our picture of TOR signaling, we expect ensemble modeling to help elucidate other insufficiently characterized cellular circuits.
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| Evidence ID | Analyze ID | Gene/Complex | Systematic Name/Complex Accession | Qualifier | Gene Ontology Term ID | Gene Ontology Term | Aspect | Annotation Extension | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Phenotype | Experiment Type | Experiment Type Category | Mutant Information | Strain Background | Chemical | Details | Reference |
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| Evidence ID | Analyze ID | Gene | Gene Systematic Name | Disease Ontology Term | Disease Ontology Term ID | Qualifier | Evidence | Method | Source | Assigned On | Reference |
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| Evidence ID | Analyze ID | Regulator | Regulator Systematic Name | Target | Target Systematic Name | Direction | Regulation of | Happens During | Regulator Type | Direction | Regulation Of | Happens During | Method | Evidence | Strain Background | Reference |
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| Site | Modification | Modifier | Source | Reference |
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| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Allele | Assay | Annotation | Action | Phenotype | SGA score | P-value | Source | Reference | Note |
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Increase the total number of rows showing on this page by using the pull-down located below the table, or use the page scroll at the table's top right to browse through the table's pages; use the arrows to the right of a column header to sort by that column; filter the table using the "Filter" box at the top of the table; click on the small "i" buttons located within a cell for an annotation to view further details about experiment type and any other genes involved in the interaction.
| Evidence ID | Analyze ID | Interactor | Interactor Systematic Name | Interactor | Interactor Systematic Name | Assay | Annotation | Action | Modification | Source | Reference | Note |
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| Complement ID | Locus ID | Gene | Species | Gene ID | Strain background | Direction | Details | Source | Reference |
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| Evidence ID | Analyze ID | Dataset | Description | Keywords | Number of Conditions | Reference |
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| Evidence ID | Analyze ID | File | Description |
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