ArticleEndocrinology2019
Alterations in Protein Kinase A Substrate Specificity as a Potential Cause of Cushing Syndrome.
Article in Endocrinology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 47 citations in OpenAlex.
- The βBritish journal of pharmacology · 2026Article
- Review
- Article
- Allosteric binding cooperativity in kinases signaling, signalopathies, and drug development.Current opinion in structural biology · 2025Review
- Protein kinase A is a dependent factor and therapeutic target in mouse models of fibrous dysplasia.Nature communications · 2025Article
- Local and distal changes in dynamics are caused by an L205R Cushing's syndrome mutant in PRKACA.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Characterisation of aEndocrine oncology (Bristol, England) · 2025Article
- The molecular genetics of adrenal cushing.Hormones (Athens, Greece) · 2024Review
- Protein kinase A and local signaling in cancer.The Biochemical journal · 2024Review
- Rare correlation of somatic PRKACA mutations with pregnancy-associated aldosterone- and cortisol-producing adenomas: a case report and literature review.BMC endocrine disorders · 2024Review
- Protein Kinase A in neurological disorders.Journal of neurodevelopmental disorders · 2024Review
- Recruitment of BAG2 to DNAJ-PKAc scaffolds promotes cell survival and resistance to drug-induced apoptosis in fibrolamellar carcinoma.Cell reports · 2024Article
- Discovery of a Cushing's syndrome protein kinase A mutant that biases signaling through type I AKAPs.Science advances · 2024Article
- Classification of Cushing's syndrome PKAc mutants based upon their ability to bind PKI.The Biochemical journal · 2023Article
- An NMR portrait of functional and dysfunctional allosteric cooperativity in cAMP-dependent protein kinase A.FEBS letters · 2023Review
- Gene Mutations in Cushing's Syndrome.Molecular syndromology · 2023Review
- Mislocalization of protein kinase A drives pathology in Cushing's syndrome.Cell reports · 2022Article
- Genetic Alterations in Benign Adrenal Tumors.Biomedicines · 2022Review
- Targeted Mutational Analysis of Cortisol-Producing Adenomas.The Journal of clinical endocrinology and metabolism · 2022Article
- The Okur-Chung Neurodevelopmental Syndrome Mutation CK2Frontiers in molecular biosciences · 2022Article
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Authors and funding
8 authors at 1 institution in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cushing syndrome is a severe endocrine disorder of cortisol excess associated with major metabolic and cardiovascular sequelae. We recently identified somatic mutations in PRKACA, the gene encoding the catalytic (C) α subunit of protein kinase A (PKA), as being responsible for cortisol-producing adrenocortical adenomas (CPAs), which are a major cause of Cushing syndrome. In spite of previous studies on the two initially identified mutations (L206R, 199_200insW), the mechanisms of action of the clinically highly relevant PRKACA mutations remain poorly understood. Here, by investigating a large panel of PRKACA mutations, including all those identified so far in Cushing syndrome, we unexpectedly found that not all mutations interfere with the binding of regulatory (R) subunits as previously hypothesized. Because several mutations lie in a region of PKA Cα involved in substrate recognition, we investigated their consequences on substrate specificity by quantitative phosphoproteomics. We found that all three mutations analyzed (L206R, 200_201insV, and d244-248+E249Q) cause major changes in the preference of PKA for its targets, leading to hyperphosphorylation of several PKA substrates, most notably including histone H1.4 at Ser36, which is required for and promotes mitosis. This is reflected by a ninefold hyperphosphorylation of H1.4 in CPAs carrying the L206R mutation. Thus, our findings suggest that in addition to hampering binding to R subunits, PRKACA mutations act by altering PKA substrate specificity. These findings shed light on the molecular events leading to Cushing syndrome and illustrate how mutations altering substrate specificity of a protein kinase may cause human disease.
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