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Activating PRKACB somatic mutation in cortisol-producing adenomas.
- Source :
-
JCI insight [JCI Insight] 2018 Apr 19; Vol. 3 (8). Date of Electronic Publication: 2018 Apr 19 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- 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.
- Subjects :
- Adenoma metabolism
Adrenal Gland Neoplasms diagnostic imaging
Adrenal Gland Neoplasms pathology
Adrenal Gland Neoplasms surgery
Adrenal Insufficiency etiology
Adrenalectomy methods
Adult
Catalytic Domain genetics
Cushing Syndrome pathology
Cushing Syndrome surgery
Cyclic AMP Receptor Protein metabolism
Cyclic AMP-Dependent Protein Kinase Catalytic Subunits
Female
Holoenzymes metabolism
Humans
Mutation
Treatment Outcome
Exome Sequencing methods
Adenoma enzymology
Cushing Syndrome diagnostic imaging
Cyclic AMP-Dependent Protein Kinases genetics
Hydrocortisone metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 3
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 29669941
- Full Text :
- https://doi.org/10.1172/jci.insight.98296