Linkers of Cell Polarity and Cell Cycle Regulation in the Fission Yeast Protein Interaction Network

The study of gene and protein interaction networks has improved our understanding of the multiple, systemic levels of regulation found in eukaryotic and prokaryotic organisms. Here we carry out a large-scale analysis of the protein-protein interaction (PPI) network of fission yeast (Schizosaccharomyces pombe) and establish a method to identify ‘linker’ proteins that bridge diverse cellular processes - integrating Gene Ontology and PPI data with network theory measures. We test the method on a highly characterized subset of the genome consisting of proteins controlling the cell cycle, cell polarity and cytokinesis and identify proteins likely to play a key role in controlling the temporal changes in the localization of the polarity machinery. Experimental inspection of one such factor, the polarity-regulating RNB protein Sts5, confirms the prediction that it has a cell cycle dependent regulation. Detailed bibliographic inspection of other predicted ‘linkers’ also confirms the predictive power of the method. As the method is robust to network perturbations and can successfully predict linker proteins, it provides a powerful tool to study the interplay between different cellular processes. Analysis of protein interaction networks has been of use as a means to grapple with the complexity of the interactome of biological organisms. So far, network based approaches have only been used in a limited number of organisms due to the lack of high-throughput experiments. In this study, we investigate by graph theoretical network analysis approaches the protein-protein interaction network of fission yeast, and present a new network measure, linkerity, that predicts the ability of certain proteins to function as bridges between diverse cellular processes. We apply this linkerity measure to a highly conserved and coupled subset of the fission yeast network, consisting of the proteins that regulate cell cycle, polarized cell growth, and cell division. In depth literature analysis confirms that several proteins identified as linkers of cell polarity regulation are indeed also associated with cell cycle and/or cell division control. Similarly, experimental testing confirms that a mostly uncharacterized polarity regulator identified by the method as an important linker is regulated by the cell cycle, as predicted.