Protein Phosphorylation: An Overview

Abstract

The work of Edwin Krebs and his colleagues over a number of years culminated in the discovery of a cyclic AMP-dependent protein kinase in skeletal muscle (Walsh et al. 1968). Moreover, Krebs and his group provided strong evidence to suggest that this cyclic AMP-dependent protein kinase was involved in mediating the effects of epinephrine in the regulation of carbohydrate metabolism in skeletal muscle. Upon the appearance of this important paper by Krebs and his colleagues, Drs. Miyamoto, Kuo and I looked for and found a cyclic AMP-dependent protein kinase in mammalian brain (Miyamoto et al. 1969). Of particular interest, our results indicated that this enzyme was present in high concentration in brain and that it was greatly enriched in those subcellular fractions containing synaptic material. These results suggested that cyclic AMP-dependent protein kinase in the brain might be involved not only in regulation of carbohydrate metabolism, but also in regulation of some of the molecular processes underlying synaptic transmission, and possibly of other physiological processes occurring in the nervous system as well. For these reasons we proposed the hypothesis (Kuo and Greengard 1969), shown in Fig. 1, that in various tissues the diverse effects of cyclic AMP, both metabolic and physiological, were achieved through regulating the activity of this one class of enzyme, cyclic AMP-dependent protein kinase. According to this hypothesis, the hormone in the endocrine system or the neurotransmitter in the nervous system activates an adenylate cyclase; the activated adenylate cyclase causes an increased conversion of ATP to cyclic AMP; the newly formed cyclic AMP activates a cyclic AMP-dependent protein kinase; the activated protein kinase causes the phosphorylation of a substrate protein, converting it from the dephospho-form to the phospho-form; the phosphorylated substrate, through one or more steps, leads to the metabolic or physiological response characteristic of the hormone or neurotransmitter in question.