Year	Event
1883	Casein is identified as the first phosphoprotein [19].
1907	Suzuki characterizes phytase, an enzyme that converts phytic acid to inositol and inorganic phosphate. This protein is generally accepted as the founding member of modern phosphatases [20, 21].
1923	Robinson discovers the earliest member of modern alkaline phosphatases. This enzyme has a pH optimum at the alkaline side of neutral. These phosphatases are now known to dephosphorylate a broad range of substrates including proteins, nucleic acids, and small molecules [21-23].
1932	Serinephosphoric acid is obtained from vitellin, providing a physical mechanism for phosphate's association with proteins. [24].
1943	Prosthetic group removing (PR) enzyme is found to convert phosphorylase A to phosphorylase B. Although unrecognized at the time, this was the first example of protein regulation by reversible phosphorylation and the PR enzyme was the first protein serine/threonine phosphatase characterized [25, 26].
1952	Phosphothreonine is obtained from casein [27].
1954	Burnett & Kennedy detect protein kinase activity for the first time against casein [28].
1955	Fischer & Krebs show that phosphorylase B can be converted to phosphorylase A in cell free extracts. This conversion was dependent on certain divalent metal ions and, in some conditions, ATP [29].
1955	Sutherland & Wosilait show that enzymatic inactivation of phosphorylase A is accompanied by phosphate release from phosphorylase A into solution [30].
1956	Krebs & Fischer purify “converting enzyme” from rabbit muscle extract and use it in an isolated system to convert phosphorylase B into phosphorylase A in the presence of radioactive ATP. The generated phosphorylase A is firmly bound to isotopic phosphate. The “converting enzyme” is later identified as Phosphorylase Kinase. [31].
1958	Krebs, Kent, & Fischer describe the stoichiometry of the kinase reaction converting phosphorylase B to phosphorylase A [32].
1968	Walsh, Perkin's, & Krebs identify the first protein kinase cascade. cAMP-dependent protein kinase (PKA) activates kinase by phosphorylation [33].
1975	Cohen, Watson, & Dixon demonstrate PKA phosphorylates phosphorylase kinase at specific amino acid sequences. Only 2 of 200 serines present in phosphorylase kinase are subject to phosphorylation by PKA, demonstrating a level of intrinsic specificity [34].
1975	Daile, Carnegie, & Young phosphorylate a synthetic peptide based on the basic protein of human myelin. This was the first demonstration of kinase activity against a synthetic peptide [35]. This study in combination with two subsequent papers[36, 37] using synthetic peptides to probe kinase specificity represent a major technical advance in the study of protein phosphorylation.
1979	Tyrosine phosphorylation is identified. v-Src is a protein tyrosine kinase and the first retroviral oncogene [38-40].
1988	Protein tyrosine phosphatases are purified to homogeneity for the first time and characterized [41].
1988	Sequence analysis of known protein kinases reveals a conserved catalytic domain [42].
1991	The first protein kinase crystal structure is determined [43].
1994	The first protein tyrosine phosphatase crystal structure is determined [44].
1995	The first protein serine/threonine phosphatase crystal structure is determined [45].