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Yet knowledge of the complete stress\u2010activated 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\u2010proteome changes in cells responding to salt stress, to infer the salt\u2010responsive 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 \u2018hubs\u2019 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\u2010defense genes with reduction of growth\u2010related transcripts. 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