Adaptive signal transduction within microbial cells involves a multi-faceted regulated phosphotransfer mechanism that comprises structural rearrangements of sensor histidine kinases upon ligand-binding and phosphorylation-induced conformational changes in response regulators of versatile two-component systems (TCS), arisen early in bacterial evolution. In Escherichia coli, cross-talk between the AtoS histidine kinase and the AtoC response regulator, forming the AtoSC TCS, through His → Asp phosphotransfer, activates AtoC directly to induce atoDAEB operon expression, thus modulating diverse fundamental cellular processes such as short-chain fatty acid catabolism, poly-(R)-3-hydroxybutyrate biosynthesis and chemotaxis. Among the inducers hitherto identified, acetoacetate is the classical activator. The AtoSC TCS functional modulation by polyamines, histamine and Ca2+, as well as the role of AtoC as transcriptional regulator, add new promising perspectives in the physiological significance and potential pharmacological exploitation of this TCS in cell proliferation, bacteria–host interactions, chemotaxis, and adaptation.