The structure and activity of cyclic AMP-dependent protein kinase A

Recent data concerning the activity of protein kinase A (cyclic adenosine 3',5' monophosphate-dependent protein kinase) in processes associated with gene expression and regulation, as well as general information concerning protein kinase A structure, synthesis and activity are presented in this article. Protein kinase A is a tetrameric protein comprising two regulatory and two catalytic subunits. The enzyme is activated by binding cAMP to the regulatory subunit, dissociation of the holoenzyme, and liberation of free catalytic subunits. Cyclic AMP is synthesized after adenylyl cyclase is activated by extracellular stimuli. Two types of protein kinase A are known, protein kinase A I and protein kinase A II. They differ in their regulatory subunits, R I and R II. Each regulatory subunit may occur in two isoforms, R I alpha, R I beta, R II alpha and R II beta. Three variants of catalytic subunits exist, C alpha, C beta and C gamma; the C beta subunit may occur in three subisoforms, C beta 1, C beta 2 and C beta 3. The R I alpha, R II alpha, and C alpha subunits are expressed ubiquitously, while the R I beta, R II beta, C beta and C gamma subunits are expressed in endocrine, neuroendocrine, neural and leukemic tissues. The activity df protein kinase A depends on cellular localization, which determines the access of the enzyme to cAMP and substrate, and on the proportions of the regulatory and catalytic subunits. Protein kinase A II is associated with cellular structures through the regulatory subunit R II, which is bound to protein kinase A anchor proteins (AKAP) or to microtubule-associated protein (MAP-2). Protein kinase A I is soluble in cellular cytosol. The protein kinase A subunits, R I alpha, R I beta, R II alpha, R II beta C alpha, C beta, and C gamma are encoded by separate genes whose promoters are activated by cAMP and bind Sp 1; they lack TATA and CAAT sequences and have several transcription start sites. Protein kinase A is involved in the expression of various proteins through the regulation of the activity and synthesis of transcription factors, cycline A, cycline-dependent protein kinase inhibitors, and phosphorylation of microtubule-associated proteins. Protein kinase A is involved in hormone synthesis and secretion. Basal cellular metabolism is affected by protein kinase A through phosphorylation and regulation of the activity of protein kinases, phosphorylases, phosphatases, protease inhibitors, and through influencing their synthesis. The cellular compartmentalization of diverse isoforms of protein kinase A, differing in activity and substrate specificity, brings about a variety of cAMP-mediated cellular responses to different hormonal stimuli.