Many signal transduction pathways comprise protein kinase cascades in which the activity of each component is controlled by phosphorylation and dephosphorylation. A new layer of kinase regulation involving nucleotide binding has now been unraveled. Phosphorylation of Akt at two regulatory sites plays a major role in kinase activation. New findings show that adenosine triphosphate (ATP) binding to Akt induces an intramolecular interaction between these phosphorylation sites and other domains in the protein, creating a cage around the phosphate group and restricting the access of phosphatases to these sites. ATP hydrolysis and substrate phosphorylation open the cage, which permits dephosphorylation and inactivation of the kinase. This switchlike mechanism provides important new insights into the biology of protein kinases.