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 Activity, expression and function of a second Drosophila protein kinase A catalytic subunit gene.

Genetics ◽  
1995 ◽  
Vol 141 (4) ◽  
pp. 1507-1520 ◽  
Author(s):  
A Meléndez ◽  
W Li ◽  
D Kalderon
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Essential Gene ◽  
Sequence Similarity ◽  
Catalytic Subunit ◽  
Subunit Gene ◽  
Drosophila Protein ◽  
Pka Catalytic Subunit ◽  
Kinase A

Abstract The DC2 gene was isolated previously on the basis of sequence similarity to DC0, the major Drosophila protein kinase A (PKA) catalytic subunit gene. We show here that the 67-kD Drosophila DC2 protein behaves as a PKA catalytic subunit in vitro. DC2 is transcribed in mesodermal anlagen of early embryos. This expression depends on dorsal but on neither twist nor snail activity. DC2 transcriptional fusions mimic this embryonic expression and are also expressed in subsets of cells in the optic lamina, wing disc and leg discs of third instar larvae. A saturation screen of a small deficiency interval containing DC2 for recessive lethal mutations yielded no DC2 alleles. We therefore isolated new deficiencies to generate deficiency trans-heterozygotes that lacked DC2 activity. These animals were viable and fertile. The absence of DC2 did not affect the viability or phenotype of imaginal disc cells lacking DC0 activity or embryonic hatching of animals with reduced DC0 activity. Furthermore, transgenes expressing DC2 from a DC0 promoter did not efficiently rescue a variety of DC0 mutant phenotypes. These observations indicate that DC2 is not an essential gene and is unlikely to be functionally redundant with DC0, which has multiple unique functions during development.

scholarly journals Cytoplasmic catalytic subunit of protein kinase A mediates cross-repression by NF-kappa B and the glucocorticoid receptor

2000 ◽  
Vol 97 (22) ◽  
pp. 11893-11898 ◽  
Author(s):  
V. Doucas ◽  
Y. Shi ◽  
S. Miyamoto ◽  
A. West ◽  
I. Verma ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Glucocorticoid Receptor ◽  
Protein Kinase A ◽  
Catalytic Subunit ◽  
Nf Kappa B ◽  
Kinase A
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