The discovery of dephosphorylation came from a series of experiments examining the enzyme phosphorylase isolated from rabbit skeletal muscle. In 1955, Edwin Krebs and Edmond Fischer used radiolabeled ATP to determine that phosphate is added to the serine residue of phosphorylase to convert it from its b to a form via phosphorylation. Subsequently, Krebs and Fischer showed that this phosphorylation is part of a kinase cascade. Finally, after purifying the phosphorylated form of the enzyme, phosphorylase a, from rabbit liver, ion exchange chromatography was used to identify phosphoprotein phosphatase I and II.
Since the discovery of these dephosphorylating proteins, the reversible nature of  phosphorylation and dephosphorylation has been associated with a broad range of functional proteins, primarily enzymatic, but also including nonenzymatic proteins. Edwin Krebs and Edmond Fischer won the 1992 Nobel Prize in Physiology or Medicine for the discovery of reversible protein phosphorylation.