Mechanisms of Aberrant PKA Activation by Cα Subunit Mutations.
Somatic mutations inPRKACA, coding for the catalytic α subunit of protein kinase A (PKA), have been recently identified as the most frequent genetic alteration in cortisol-secreting adrenocortical adenomas, which are responsible for adrenal Cushing's syndrome. The mutations identified so far lie at the interface between the catalytic (C) and regulatory (R) subunit of PKA. Detailed functional studies of the most frequent of these mutations (L206R) as well as of another one in the same region of the C subunit (199_200insW) have revealed that these mutations cause constitutive activation of PKA and lack of regulation by cAMP. This is due to interference with the binding of the R subunit, which keeps the C subunit inactive in the absence of cyclic AMP. Here, we review these recent findings, with a particular focus on the mechanisms of action ofPRKACAmutations.
Institute of Pharmacology and Toxicology, University Hospital, University of Würzburg, Würzburg, Germany.
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Calebiro
Institute of Pharmacology and Toxicology, University Hospital, University of Würzburg, Würzburg, Germany.
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Bathon
Department of Medicine I, Endocrine and Diabetes Unit, University Hospital, University of Würzburg, Würzburg, Germany.
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Weigand
D000306:Adrenal Cortex Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D018246:Adrenocortical Adenoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D019943:Amino Acid Substitution; D000818:Animals; D003480:Cushing Syndrome / Q000453:epidemiology / Q000235:genetics / Q000473:pathology; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D015290:Second Messenger Systems / Q000235:genetics
D009363:Neoplasm Proteins; D000242:Cyclic AMP; D054751:Cyclic AMP-Dependent Protein Kinase Catalytic Subunits; C517757:PRKACA protein, human