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 Ca(2+), 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.