Activating PRKACB somatic mutation in cortisol-producing adenomas

Research output: Contribution to journalArticlepeer-review

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Activating PRKACB somatic mutation in cortisol-producing adenomas. / Espiard, Stéphanie; Knape, Matthias J; Bathon, Kerstin; Assié, Guillaume; Rizk-Rabin, Marthe; Faillot, Simon; Luscap-Rondof, Windy; Abid, Daniel; Guignat, Laurence; Calebiro, Davide; Herberg, Friedrich W; Stratakis, Constantine A; Bertherat, Jérôme.

In: JCI Insight, Vol. 3, No. 8, 19.04.2018.

Research output: Contribution to journalArticlepeer-review

Harvard

Espiard, S, Knape, MJ, Bathon, K, Assié, G, Rizk-Rabin, M, Faillot, S, Luscap-Rondof, W, Abid, D, Guignat, L, Calebiro, D, Herberg, FW, Stratakis, CA & Bertherat, J 2018, 'Activating PRKACB somatic mutation in cortisol-producing adenomas', JCI Insight, vol. 3, no. 8. https://doi.org/10.1172/jci.insight.98296

APA

Espiard, S., Knape, M. J., Bathon, K., Assié, G., Rizk-Rabin, M., Faillot, S., Luscap-Rondof, W., Abid, D., Guignat, L., Calebiro, D., Herberg, F. W., Stratakis, C. A., & Bertherat, J. (2018). Activating PRKACB somatic mutation in cortisol-producing adenomas. JCI Insight, 3(8). https://doi.org/10.1172/jci.insight.98296

Vancouver

Espiard S, Knape MJ, Bathon K, Assié G, Rizk-Rabin M, Faillot S et al. Activating PRKACB somatic mutation in cortisol-producing adenomas. JCI Insight. 2018 Apr 19;3(8). https://doi.org/10.1172/jci.insight.98296

Author

Espiard, Stéphanie ; Knape, Matthias J ; Bathon, Kerstin ; Assié, Guillaume ; Rizk-Rabin, Marthe ; Faillot, Simon ; Luscap-Rondof, Windy ; Abid, Daniel ; Guignat, Laurence ; Calebiro, Davide ; Herberg, Friedrich W ; Stratakis, Constantine A ; Bertherat, Jérôme. / Activating PRKACB somatic mutation in cortisol-producing adenomas. In: JCI Insight. 2018 ; Vol. 3, No. 8.

Bibtex

@article{f8a99e618eeb4e4eb18a288e64f47aac,
title = "Activating PRKACB somatic mutation in cortisol-producing adenomas",
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.",
author = "St{\'e}phanie Espiard and Knape, {Matthias J} and Kerstin Bathon and Guillaume Assi{\'e} and Marthe Rizk-Rabin and Simon Faillot and Windy Luscap-Rondof and Daniel Abid and Laurence Guignat and Davide Calebiro and Herberg, {Friedrich W} and Stratakis, {Constantine A} and J{\'e}r{\^o}me Bertherat",
year = "2018",
month = apr,
day = "19",
doi = "10.1172/jci.insight.98296",
language = "English",
volume = "3",
journal = "JCI Insight",
issn = "2379-3708",
publisher = "American Society for Clinical Investigation",
number = "8",

}

RIS

TY - JOUR

T1 - Activating PRKACB somatic mutation in cortisol-producing adenomas

AU - Espiard, Stéphanie

AU - Knape, Matthias J

AU - Bathon, Kerstin

AU - Assié, Guillaume

AU - Rizk-Rabin, Marthe

AU - Faillot, Simon

AU - Luscap-Rondof, Windy

AU - Abid, Daniel

AU - Guignat, Laurence

AU - Calebiro, Davide

AU - Herberg, Friedrich W

AU - Stratakis, Constantine A

AU - Bertherat, Jérôme

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.98296

DO - 10.1172/jci.insight.98296

M3 - Article

C2 - 29669941

VL - 3

JO - JCI Insight

JF - JCI Insight

SN - 2379-3708

IS - 8

ER -