The allosteric interactions and regulation of molecular chaperones and protein kinases allow for molecular communication and event coupling in signal transduction networks. We report the results of integrative systems biology studies of the Hsp90 chaperone and protein kinases with an atomic level analysis of the communication pathways regulating conformational equilibrium of theses protein systems in signaling networks. Biophysical modeling of allosteric regulation in the protein kinases has offered additional insights into organizing principles of kinase activation by molecular chaperones that may be orchestrated by a cross-talk between key regulatory regions. The results of biophysical and computational systems biology analyses combined with proteomics experiments have been integrated into a graph-based network model of allosteric regulation. The evolution of protein structure networks in molecular chaperones and protein kinases during allosteric activation has revealed the increased cooperativity reflecting a preferential attachment of allosterically interacting functional sites. Among our primary findings is the emerging evidence that a small number of functional motifs may be utilized by the chaperone and protein kinases to act collectively as central regulators of the intermolecular communications, ATP hydrolysis, and protein client binding in signaling networks. Integration of computational systems biology and machine learning analysis of the Hsp90 interactions with oncogenic kinase mutants is then used to construct models of allosteric regulation of oncogenic proteins by molecular chaperones in signaling cascades. A computational synthetic biology framework is proposed for design and re-engineering signal transduction networks and pathways that involve cross-talk between molecular chaperones and protein kinase clients. We have also analyzed mechanisms by which kinase drugs and allosteric Hsp90 modulators can act synergistically and exert their pharmacological effect by depriving the client kinase of access to the molecular chaperone.