Activating PRKACB somatic mutation in cortisol-producing adenomas.

Autor:	Espiard S; Cochin Institute, Paris Descartes University, CNRS (UMR 8104)/Inserm (U1016), Paris, France.; Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA., Knape MJ; University of Kassel, Department of Biochemistry, Kassel, Germany., Bathon K; Institute of Pharmacology and Toxicology and Bio-Imaging Center/Rudolf Virchow Center, University of Würzburg, Würzburg, Germany., Assié G; Cochin Institute, Paris Descartes University, CNRS (UMR 8104)/Inserm (U1016), Paris, France.; Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France., Rizk-Rabin M; Cochin Institute, Paris Descartes University, CNRS (UMR 8104)/Inserm (U1016), Paris, France., Faillot S; Cochin Institute, Paris Descartes University, CNRS (UMR 8104)/Inserm (U1016), Paris, France., Luscap-Rondof W; Cochin Institute, Paris Descartes University, CNRS (UMR 8104)/Inserm (U1016), Paris, France., Abid D; University of Kassel, Department of Biochemistry, Kassel, Germany., Guignat L; Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France., Calebiro D; Institute of Pharmacology and Toxicology and Bio-Imaging Center/Rudolf Virchow Center, University of Würzburg, Würzburg, Germany.; Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom.; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, United Kingdom., Herberg FW; University of Kassel, Department of Biochemistry, Kassel, Germany., Stratakis CA; Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA., Bertherat J; Cochin Institute, Paris Descartes University, CNRS (UMR 8104)/Inserm (U1016), Paris, France.; Center for Rare Adrenal Diseases, Endocrinology Department, Cochin Hospital, Assistance Publique Hôpitaux de Paris, Paris, France.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2018 Apr 19; Vol. 3 (8). Date of Electronic Publication: 2018 Apr 19 (Print Publication: 2018).
DOI:	10.1172/jci.insight.98296
Abstrakt:	Mutations in the gene encoding the protein kinase A (PKA) catalytic subunit α have been found to be responsible for cortisol-producing adenomas (CPAs). In this study, we identified by whole-exome sequencing the somatic mutation p.S54L in the PRKACB gene, encoding the catalytic subunit β (Cβ) of PKA, in a CPA from a patient with severe Cushing syndrome. Bioluminescence resonance energy transfer and surface plasmon resonance assays revealed that the mutation hampers formation of type I holoenzymes and that these holoenzymes were highly sensitive to cAMP. PKA activity, measured both in cell lysates and with recombinant proteins, based on phosphorylation of a synthetic substrate, was higher under basal conditions for the mutant enzyme compared with the WT, while maximal activity was lower. These data suggest that at baseline the PRKACB p.S54L mutant drove the adenoma cells to higher cAMP signaling activity, probably contributing to their autonomous growth. Although the role of PRKACB in tumorigenesis has been suggested, we demonstrated for the first time to our knowledge that a PRKACB mutation can lead to an adrenal tumor. Moreover, this observation describes another mechanism of PKA pathway activation in CPAs and highlights the particular role of residue Ser54 for the function of PKA.
Databáze:	MEDLINE
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