Abstract
Embedded within large-scale protein interaction networks are signaling pathways that encode response cascades in the cell. Unfortunately, even for well-studied species like S. cerevisiae, only a fraction of all true protein interactions are known, which makes it difficult to reason about the exact flow of signals and the corresponding causal relations in the network. To help address this problem, we introduce a framework for predicting new interactions that aid connectivity between upstream proteins (sources) and downstream transcription factors (targets) of a particular pathway. Our algorithms attempt to globally minimize the distance between sources and targets by finding a small set of shortcut edges to add to the network. Unlike existing algorithms for predicting general protein interactions, by focusing on proteins involved in specific responses our approach homes-in on pathway-consistent interactions. We applied our method to extend pathways in osmotic stress response in yeast and identified several missing interactions, some of which are supported by published reports. We also performed experiments that support a novel interaction not previously reported. Our framework is general and may be applicable to edge prediction problems in other domains.
Highlights
Networks of protein interactions can reveal how complex molecular processes are activated in the cell
Networks of protein interactions encode a variety of molecular processes occurring in the cell
Pathways are initiated by upstream proteins that receive signals from the environment and trigger a cascade of information to downstream proteins
Summary
Networks of protein interactions can reveal how complex molecular processes are activated in the cell. Even for model species, only a fraction of true physical interactions are known [1,2] and experimental verification of all remaining potential interactions is unlikely in the near future. Interactions are often condition- or tissue-specific [3] while current experimental methods often focus on one condition and one cell type [4]. Signaling pathways are subnetworks of proteins that communicate via a series of interactions and are often only activated under specific conditions (e.g. stress response, development, etc.). Pathways are often conserved, studying their interactions in model organisms may help elucidate cellular response mechanisms in other organisms [8]
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