Pathway connectivity and signaling coordination in the yeast stress‐activated signaling network

Abstract

Stressed cells coordinate a multi‐faceted response spanning many levels of physiology. Yet knowledge of the complete stress‐activated regulatory network as well as design principles for signal integration remains incomplete. We developed an experimental and computational approach to integrate available protein interaction data with gene fitness contributions, mutant transcriptome profiles, and phospho‐proteome changes in cells responding to salt stress, to infer the salt‐responsive signaling network in yeast. The inferred subnetwork presented many novel predictions by implicating new regulators, uncovering unrecognized crosstalk between known pathways, and pointing to previously unknown ‘hubs’ of signal integration. We exploited these predictions to show that Cdc14 phosphatase is a central hub in the network and that modification of RNA polymerase II coordinates induction of stress‐defense genes with reduction of growth‐related transcripts. We find that the orthologous human network is enriched for cancer‐causing genes, underscoring the importance of the subnetwork's predictions in understanding stress biology. image An experimental and computational pipeline was developed to infer the yeast salt‐activated signaling network. The resulting network provides new insights into how cells integrate upstream signals to produce a coordinated transcriptional response to stress. An integer linear programming method for integrating disparate high‐throughput datasets was developed and used to infer the yeast signaling network activated by salt stress. The network shows high connectivity between what are typically considered distinct pathways. The phosphatase Cdc14 coordinates several aspects of the stress response, and RNA Pol II modification is a key regulatory point for the induction of stress‐defense genes with repression of growth‐related genes. The orthologous human network is enriched for cancer‐related genes, underscoring the importance of stress‐responsive signaling networks in human disease biology.