The role of protein phosphorylation in the hormonal control of enzyme activity

Abstract

A major goal of molecular pharmacology is to account for the extreme biological potency and great diversity of action of hormones. These extracellular signals circulate in the blood at nanomolar or subnanomolar concentrations, and yet within seconds they can produce millimolar changes in the levels of metabolites. Hormonal stimuli must therefore be amplified a million-fold or more following their interaction with plasma-membrane-bound rcceptors. Furthermore, the actions of a hormone are nearly always pleiotropic, affecting many processes within a givcn target cell, and eliciting quite distinct responses in diffcrent cell types.Amplification and diversity in hormone action are achieved by two principal mechanisms, namely the reversible phosphorylation of proteins ( Fig. 1) and the formation of molecular species termed 'second messengers'. Many key regulatory proteins exist in either a phosphorylated or a dephosphorylated form, their steady-state levels of phosphorylation reflecting the relative activities of the protein kinases and phosphatases that catalyse the interconversion process. Phosphorylation of seryl, threonyl, or occasionally tyrosyl residues, trigger small conformational changes in these proteins, which alter their biological properties. Hormones transmit information to the interior of the cell by activating transmembrane signalling systems that control production of a relatively small number of chemical mediators or second messengers. These substances regulate protein kinase and phosphatase activities, and so alter the phosphorylation states of many intracellular proteins, explaining the diversity of action of hormones [I, 21.Amplification of hormonal stimuli is achieved at several levels. Firstly, second messengers are formed in micromolar concentrations in response to nanomolar levels of hormones.Secondly, each molecule of protein kinase (or phosphatase) may catalyse the phosphorylation (or dephosphorylation) of many molecules of regulatory protein. Thirdly, in the case of regulatory proteins that are enzymes, each molecule of enzyme may catalyse the transformation of many molecules of substrate to product.In this lecture I will review the role of protein phosphorylation and dephosphorylation in the regulation of cellular activity, with emphasis on the hormonal control of metabolic pathways where the intracellular targets for phosphorylation are enzymes. However, while these systems are the best understood in molecular terms, it should be emphasized that phosphorylation also modifies the functions of proteins that are not enzymes and that almost all cellular processes are controlled by this versatile post-translational modification. Cyclic-A M P-dependcw t protein kinuseA large number of hormones exert their effects by increasing or decreasing the concentration of cyclic AMP, and the transmcmbrane signalling systems involved in the formation of this second messenger are starting to be understood in molecular detail [3]. The effects of cyclic AMP on metabolic pathways are mediated by cyclic-AMP-dep...

A beta-adrenergic receptor kinase-like enzyme is involved in olfactory signal termination.

“…In this model, the action of 3ARK-2 would be substrate-controlled, a mechanism characteristic for the structurally related rhodopsin kinase (23,24). (ii) PKA might directly phosphorylate and thus activate /ARK-2; this type ofreaction would resemble a kinase cascade, as, for example, described for regulation of metabolic pathways (25). (iii) PKA may phosphorylate and thereby inactivate endogenous inhibitors of a f3ARK-2-like kinase.…”

d‐Glyceraldehyde‐3‐phosphate dehydrogenase purified from rabbit muscle contains phosphotyrosine

“…Protein phosphorylation is the most widely occurring post-translational modification used in the control of biological processes [1]; it is believed to constitute one of the mechanisms for the regulation of glycol),sis and gluconeogenesis [2]. A number of glycolytic enzymes (pyruvate kinase, 6-phospho fr ucto-1 -kinase, 6-phosphofructo-2-kinase, fructose-l,6-bisphosphatase) were shown to be substrates for various protein kinases [3][4][5][6][7].…”

Expression of four types of human tyrosine hydroxylase in COS cells

“…TH is the first and rate-limiting enzyme in the pathway of catecholamine biosynthesis, its enzyme activity being regulated by protein phosphorylation [ 1,2] and by some organic compounds [3-51. Recently, four types of human TH (types l-4) have been found by cDNA cloning . This protein diversity is generated through alternative splicing from a single gene [9-111.…”