scholarly journals Expression of Serotonin7Receptor and Coupling of Ectopic Receptors to Protein Kinase A and Ionic Currents in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia Causing Cushing’s Syndrome

2006 ◽  
Vol 91 (11) ◽  
pp. 4578-4586 ◽  
Author(s):  
Estelle Louiset ◽  
Vincent Contesse ◽  
Lionel Groussin ◽  
Dorthe Cartier ◽  
Céline Duparc ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing’S Syndrome ◽  
Ionic Currents ◽  
Cushing's Syndrome ◽  
Adrenal Hyperplasia ◽  
Kinase A

Novel Somatic Mutations in the Catalytic Subunit of the Protein Kinase A as a Cause of Adrenal Cushing's Syndrome: A European Multicentric Study

2014 ◽  
Vol 99 (10) ◽  
pp. E2093-E2100 ◽  
Author(s):  
Guido Di Dalmazi ◽  
Caroline Kisker ◽  
Davide Calebiro ◽  
Massimo Mannelli ◽  
Letizia Canu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing’S Syndrome ◽  
Somatic Mutations ◽  
Cushing's Syndrome ◽  
Catalytic Subunit ◽  
Multicentric Study ◽  
Kinase A

scholarly journals Structural insights into mis-regulation of protein kinase A in human tumors

2015 ◽  
Vol 112 (5) ◽  
pp. 1374-1379 ◽  
Author(s):  
Jonah Cheung ◽  
Christopher Ginter ◽  
Michael Cassidy ◽  
Matthew C. Franklin ◽  
Michael J. Rudolph ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing’S Syndrome ◽  
Biochemical Characterization ◽  
Cushing's Syndrome ◽  
Regulatory Subunit ◽  
Recurrent Mutations ◽  
Distinct Disease ◽  
Genomic Studies ◽  
Kinase A

The extensively studied cAMP-dependent protein kinase A (PKA) is involved in the regulation of critical cell processes, including metabolism, gene expression, and cell proliferation; consequentially, mis-regulation of PKA signaling is implicated in tumorigenesis. Recent genomic studies have identified recurrent mutations in the catalytic subunit of PKA in tumors associated with Cushing’s syndrome, a kidney disorder leading to excessive cortisol production, and also in tumors associated with fibrolamellar hepatocellular carcinoma (FL-HCC), a rare liver cancer. Expression of a L205R point mutant and a DnaJ–PKA fusion protein were found to be linked to Cushing's syndrome and FL-HCC, respectively. Here we reveal contrasting mechanisms for increased PKA signaling at the molecular level through structural determination and biochemical characterization of the aberrant enzymes. In the Cushing’s syndrome disorder, we find that the L205R mutation abolishes regulatory-subunit binding, leading to constitutive, cAMP-independent signaling. In FL-HCC, the DnaJ–PKA chimera remains under regulatory subunit control; however, its overexpression from the DnaJ promoter leads to enhanced cAMP-dependent signaling. Our findings provide a structural understanding of the two distinct disease mechanisms and they offer a basis for designing effective drugs for their treatment.

scholarly journals Cushing’s syndrome driver mutation disrupts protein kinase A allosteric network, altering both regulation and substrate specificity

2019 ◽  
Vol 5 (8) ◽  
pp. eaaw9298 ◽  
Author(s):  
Caitlin Walker ◽  
Yingjie Wang ◽  
Cristina Olivieri ◽  
Adak Karamafrooz ◽  
Jordan Casby ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Substrate Specificity ◽  
Protein Kinase A ◽  
Cushing’S Syndrome ◽  
Genetic Alterations ◽  
Cushing's Syndrome ◽  
Single Mutation ◽  
Α Subunit ◽  
Adrenocortical Adenomas ◽  
Kinase A

Genetic alterations in the PRKACA gene coding for the catalytic α subunit of the cAMP-dependent protein kinase A (PKA-C) are linked to cortisol-secreting adrenocortical adenomas, resulting in Cushing’s syndrome. Among those, a single mutation (L205R) has been found in up to 67% of patients. Because the x-ray structures of the wild-type and mutant kinases are essentially identical, the mechanism explaining aberrant function of this mutant remains under active debate. Using NMR spectroscopy, thermodynamics, kinetic assays, and molecular dynamics simulations, we found that this single mutation causes global changes in the enzyme, disrupting the intramolecular allosteric network and eliciting losses in nucleotide/pseudo-substrate binding cooperativity. Remarkably, by rewiring its internal allosteric network, PKA-CL205R is able to bind and phosphorylate non-canonical substrates, explaining its changes in substrate specificity. Both the lack of regulation and change in substrate specificity reveal the complex role of this mutated kinase in the formation of cortisol-secreting adrenocortical adenomas.

Is disrupted nucleotide-substrate cooperativity a common trait for Cushing's syndrome driving mutations of protein kinase A?

2021 ◽  
pp. 167123
Author(s):  
Caitlin Walker ◽  
Yingjie Wang ◽  
Cristina Olivieri ◽  
Manu V.S ◽  
Jiali Gao ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing’S Syndrome ◽  
Cushing's Syndrome ◽  
Kinase A

scholarly journals Molecular Genetic and Genomic Alterations in Cushing’s Syndrome and Primary Aldosteronism

2021 ◽  
Vol 12 ◽  
Author(s):  
Crystal D. C. Kamilaris ◽  
Constantine A. Stratakis ◽  
Fady Hannah-Shmouni
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing’S Syndrome ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Genetic Alterations ◽  
Cushing's Syndrome ◽  
Adrenocortical Tumors ◽  
Pathogenic Variants ◽  
Kinase A

The genetic alterations that cause the development of glucocorticoid and/or mineralocorticoid producing benign adrenocortical tumors and hyperplasias have largely been elucidated over the past two decades through advances in genomics. In benign aldosterone-producing adrenocortical tumors and hyperplasias, alteration of intracellular calcium signaling has been found to be significant in aldosterone hypersecretion, with causative defects including those in KCNJ5, ATP1A1, ATP2B3, CACNA1D, CACNA1H, and CLCN2. In benign cortisol-producing adrenocortical tumors and hyperplasias abnormal cyclic adenosine monophosphate-protein kinase A signaling has been found to play a central role in tumorigenesis, with pathogenic variants in GNAS, PRKAR1A, PRKACA, PRKACB, PDE11A, and PDE8B being implicated. The role of this signaling pathway in the development of Cushing’s syndrome and adrenocortical tumors was initially discovered through the study of the underlying genetic defects causing the rare multiple endocrine neoplasia syndromes McCune-Albright syndrome and Carney complex with subsequent identification of defects in genes affecting the cyclic adenosine monophosphate-protein kinase A pathway in sporadic tumors. Additionally, germline pathogenic variants in ARMC5, a putative tumor suppressor, were found to be a cause of cortisol-producing primary bilateral macronodular adrenal hyperplasia. This review describes the genetic causes of benign cortisol- and aldosterone-producing adrenocortical tumors.

scholarly journals 17q22–24 Chromosomal Losses and Alterations of Protein Kinase A Subunit Expression and Activity in Adrenocorticotropin-Independent Macronodular Adrenal Hyperplasia

2006 ◽  
Vol 91 (9) ◽  
pp. 3626-3632 ◽  
Author(s):  
Isabelle Bourdeau ◽  
Ludmila Matyakhina ◽  
Sotirios G. Stergiopoulos ◽  
Fabiano Sandrini ◽  
Sosipatros Boikos ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing Syndrome ◽  
Carney Complex ◽  
Chromosome 17 ◽  
Regulatory Subunit ◽  
Adrenal Tumors ◽  
Adrenal Hyperplasia ◽  
Subunit Expression ◽  
Kinase A

Abstract Context: Primary adrenocortical hyperplasias leading to Cushing syndrome include primary pigmented nodular adrenocortical disease and ACTH-independent macronodular adrenal hyperplasia (AIMAH). Inactivating mutations of the 17q22–24-located PRKAR1A gene, coding for the type 1A regulatory subunit of protein kinase A (PKA), cause primary pigmented nodular adrenocortical disease and the multiple endocrine neoplasia syndrome Carney complex. PRKAR1A mutations and 17q22–24 chromosomal losses have been found in sporadic adrenal tumors and are associated with aberrant PKA signaling. Objective: The objective of the study was to examine whether somatic 17q22–24 changes, PRKAR1A mutations, and/or PKA abnormalities are present in AIMAH. Patients: We studied fourteen patients with Cushing syndrome due to AIMAH. Methods: Fluorescent in situ hybridization with a PRKAR1A-specific probe was used for investigating chromosome 17 allelic losses. The PRKAR1A gene was sequenced in all samples, and tissue was studied for PKA activity, cAMP responsiveness, and PKA subunit expression. Results: We found 17q22–24 allelic losses in 73% of the samples. There were no PRKAR1A-coding sequence mutations. The RIIβ PKA subunit was overexpressed by mRNA, whereas the RIα, RIβ, RIIα, and Cα PKA subunits were underexpressed. These findings were confirmed by immunohistochemistry. Total PKA activity and free PKA activity were higher in AIMAH than normal adrenal glands, consistent with the up-regulation of the RIIβ PKA subunit. Conclusions: PRKAR1A mutations are not found in AIMAH. Somatic losses of the 17q22–24 region and PKA subunit and enzymatic activity changes show that PKA signaling is altered in AIMAH in a way that is similar to that of other adrenal tumors with 17q losses or PRKAR1A mutations.

scholarly journals PKA Cα subunit mutation triggers caspase-dependent RIIβ subunit degradation via Ser114 phosphorylation

2021 ◽  
Vol 7 (8) ◽  
pp. eabd4176
Author(s):  
Isabel Weigand ◽  
Cristina L. Ronchi ◽  
Jens T. Vanselow ◽  
Kerstin Bathon ◽  
Kerstin Lenz ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cushing’S Syndrome ◽  
Molecular Mechanisms ◽  
Cushing's Syndrome ◽  
Regulatory Subunit ◽  
Cortisol Secretion ◽  
Adrenocortical Cells ◽  
Protein Levels ◽  
Adrenocortical Adenomas ◽  
Kinase A

Mutations in the PRKACA gene are the most frequent cause of cortisol-producing adrenocortical adenomas leading to Cushing’s syndrome. PRKACA encodes for the catalytic subunit α of protein kinase A (PKA). We already showed that PRKACA mutations lead to impairment of regulatory (R) subunit binding. Furthermore, PRKACA mutations are associated with reduced RIIβ protein levels; however, the mechanisms leading to reduced RIIβ levels are presently unknown. Here, we investigate the effects of the most frequent PRKACA mutation, L206R, on regulatory subunit stability. We find that Ser114 phosphorylation of RIIβ is required for its degradation, mediated by caspase 16. Last, we show that the resulting reduction in RIIβ protein levels leads to increased cortisol secretion in adrenocortical cells. These findings reveal the molecular mechanisms and pathophysiological relevance of the R subunit degradation caused by PRKACA mutations, adding another dimension to the deregulation of PKA signaling caused by PRKACA mutations in adrenal Cushing’s syndrome.

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