Cellular regulation by protein phosphorylation.

A historical account of the discovery of reversible protein phosphorylation is presented. This process was uncovered in the mid 1950s in a study undertaken with Edwin G. Krebs to elucidate the complex hormonal regulation of skeletal muscle glycogen phosphorylase. Contrary to the known activation of this enzyme by AMP which serves as an allosteric effector, its hormonal regulation results from a phosphorylation of the protein by phosphorylase kinase following the activation of the latter by Ca(2+) and ATP. The study led to the establishment of the first hormonal cascade of successive enzymatic reactions, kinases acting on kinases, initiated by cAMP discovered by Earl Sutherland. It also showed how two different physiological processes, carbohydrate metabolism and muscle contraction, could be regulated in concert.

Earl Sutherland (1915-1974) [corrected] and the discovery of cyclic AMP.

In 1945, Earl Sutherland (1915-1974) [corrected] and associates began studies of the mechanism of hormone-induced glycogen breakdown in the liver. In 1956, their efforts culminated in the identification of cyclic AMP, an ancient molecule generated in many cell types in response to hormonal and other extracellular signals. Cyclic AMP, the original "second messenger," transmits such signals through pathways that regulate a diversity of cellular functions and capabilities: metabolic processes such as lipolysis and glycogenolysis; hormone secretion; the permeability of ion channels; gene expression; cell proliferation and survival. Indeed, it can be argued that the discovery of cyclic AMP initiated the study of intracellular signaling pathways, a major focus of contemporary biomedical inquiry. This review presents relevant details of Sutherland's career; summarizes key contributions of his mentors, Carl and Gerti Cori, to the knowledge of glycogen metabolism (contributions that were the foundation for his own research); describes the experiments that led to his identification, isolation, and characterization of cyclic AMP; assesses the significance of his work; and considers some aspects of the impact of cyclic nucleotide research on clinical medicine.

Oscillations and waves of cyclic AMP in Dictyostelium: a prototype for spatio-temporal organization and pulsatile intercellular communication.

The amoebae Dictyostelium discoideum aggregate after starvation in a wavelike manner in response to periodic pulses of cyclic AMP (cAMP) secreted by cells which behave as aggregation centers. In addition to autonomous oscillations, the cAMP signaling system that controls aggregation is also capable of excitable behavior, which consists in the transient amplification of suprathreshold pulses of extracellular cAMP. Since the first theoretical model for slime mold aggregation proposed by Keller and Segel in 1970, many theoretical studies have addressed various aspects of the mechanism and function of cAMP signaling in Dictyostelium. This paper presents a brief overview of these developments as well as some reminiscences of the author's collaboration with Lee Segel in modeling the dynamics of cAMP relay and oscillations. Considered in turn are models for cAMP signaling in Dictyostelium, the developmental path followed by the cAMP signaling system after starvation, the frequency encoding of cAMP signals, and the origin of concentric or spiral waves of cAMP.

Anchored cAMP signaling: onward and upward - a short history of compartmentalized cAMP signal transduction.

Intracellular signal transduction pathways require a high degree of spatial and temporal resolution in order to deliver the appropriate outputs. Specific signaling mediated by the ubiquitous second messenger cAMP and its effector, the cAMP-dependent protein kinase (PKA), is governed by the spatial organization of different pathway components by A-kinase anchoring proteins (AKAPs). This review discusses the history and future of anchored cAMP signaling pathways.

From cAMP to adenosine: an illuminating shift of focus.

In a remarkable career, straddling five decades, John Phillis pursued with fierce determination and exceptional energy the main goal of his scientific life, to throw light on the chemical agents that control brain function. Starting in Australia, he settled in North America, first in Canada, then in the USA, where his long tenure at Wayne State brought his career to its culmination.

Cyclic nucleotide research -- still expanding after half a century.

Since the discovery in 1957 that cyclic AMP acts as a second messenger for the hormone adrenaline, interest in this molecule and its companion, cyclic GMP, has grown. Over a period of nearly 50 years, research into second messengers has provided a framework for understanding transmembrane signal transduction, receptor-effector coupling, protein-kinase cascades and downregulation of drug responsiveness. The breadth and impact of this work is reflected by five different Nobel prizes.

The origins of protein phosphorylation.

The reversible phosphorylation of proteins is central to the regulation of most aspects of cell function but, even after the first protein kinase was identified, the general significance of this discovery was slow to be appreciated. Here I review the discovery of protein phosphorylation and give a personal view of the key findings that have helped to shape the field as we know it today.