Forty-six years ago, Edwin Krebs and colleagues changed the way researchers understood the regulation of protein activity. In a landmark paper, these authors described the regulation of glycogen phosphorylase by attachment of a phosphate group.1 Four years later, these same authors discovered that this phosphorylation event was mediated by the enzyme glycogen phosphorylase kinase (kinases are enzymes that catalyze the transfer of a phosphate group from ATP to a substrate protein).2 And nine years after that, they demonstrated that glycogen phosphorylase kinase was itself regulated by glycogen phosphorylase kinase kinase (now referred to as cAMP-dependent protein kinase, cAPK).3

Other researchers partially explained the relationship of the cascading control of these enzymes with the second messenger concept, proposed in 1955.4 The second messenger hypothesis explains how an extracellular signal (such as hormone binding to a receptor) can be translated into a rapid, strong, intracellular response. The activation...

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