Mutations of the gene encoding the protein kinase A type I-α regulatory subunit in patients with the Carney complex

10.1038/79238 ◽  
2000 ◽  
Vol 26 (1) ◽  
pp. 89-92 ◽  
Author(s):  
Lawrence S. Kirschner ◽  
J. Aidan Carney ◽  
Svetlana D. Pack ◽  
Susan E. Taymans ◽  
Christoforos Giatzakis ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Type I ◽  
Gene Encoding ◽  
Kinase A

Protein kinase A and its role in human neoplasia: the Carney complex paradigm.

2004 ◽  
Vol 11 (2) ◽  
pp. 265-280 ◽  
Author(s):  
I Bossis ◽  
A Voutetakis ◽  
T Bei ◽  
F Sandrini ◽  
K J Griffin ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Cushing Syndrome ◽  
Skin Pigmentation ◽  
Suppressor Gene ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Extensive Literature ◽  
Bilateral Adrenal Hyperplasia ◽  
Kinase A

The type 1 alpha regulatory subunit (R1alpha) of cAMP-dependent protein kinase A (PKA) (PRKAR1A) is an important regulator of the serine-threonine kinase activity catalyzed by the PKA holoenzyme. Carney complex (CNC) describes the association 'of spotty skin pigmentation, myxomas, and endocrine overactivity'; CNC is in essence the latest form of multiple endocrine neoplasia to be described and affects the pituitary, thyroid, adrenal and gonadal glands. Primary pigmented nodular adrenocortical disease (PPNAD), a micronodular form of bilateral adrenal hyperplasia that causes a unique, inherited form of Cushing syndrome, is also the most common endocrine manifestation of CNC. CNC and PPNAD are genetically heterogeneous but one of the responsible genes is PRKAR1A, at least for those families that map to 17q22-24 (the chromosomal region that harbors PRKAR1A). CNC and/or PPNAD are the first human diseases to be caused by mutations in one of the subunits of the PKA holoenzyme. Despite the extensive literature on R1alpha and PKA, little is known about their potential involvement in cell cycle regulation, growth and/or proliferation. The presence of inactivating germline mutations and the loss of its wild-type allele in CNC lesions indicated that PRKAR1A could function as a tumor-suppressor gene in these tissues. However, there are conflicting data in the literature about PRKAR1A's role in human neoplasms, cancer cell lines and animal models. In this report, we review briefly the genetics of CNC and focus on the involvement of PRKAR1A in human tumorigenesis in an effort to reconcile the often diametrically opposite reports on R1alpha.

scholarly journals Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations

2021 ◽  
Vol 118 (21) ◽  
pp. e2024716118
Author(s):  
Naeimeh Jafari ◽  
Jason Del Rio ◽  
Madoka Akimoto ◽  
Jung Ah Byun ◽  
Stephen Boulton ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Molecular Mechanisms ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Regulatory Subunits ◽  
Inhibitory Function ◽  
Wide Range ◽  
Liver Cancers ◽  
Kinase A

Familial mutations of the protein kinase A (PKA) R1α regulatory subunit lead to a generalized predisposition for a wide range of tumors, from pituitary adenomas to pancreatic and liver cancers, commonly referred to as Carney complex (CNC). CNC mutations are known to cause overactivation of PKA, but the molecular mechanisms underlying such kinase overactivity are not fully understood in the context of the canonical cAMP-dependent activation of PKA. Here, we show that oligomerization-induced sequestration of R1α from the catalytic subunit of PKA (C) is a viable mechanism of PKA activation that can explain the CNC phenotype. Our investigations focus on comparative analyses at the level of structure, unfolding, aggregation, and kinase inhibition profiles of wild-type (wt) PKA R1α, the A211D and G287W CNC mutants, as well as the cognate acrodysostosis type 1 (ACRDYS1) mutations A211T and G287E. The latter exhibit a phenotype opposite to CNC with suboptimal PKA activation compared with wt. Overall, our results show that CNC mutations not only perturb the classical cAMP-dependent allosteric activation pathway of PKA, but also amplify significantly more than the cognate ACRDYS1 mutations nonclassical and previously unappreciated activation pathways, such as oligomerization-induced losses of the PKA R1α inhibitory function.

Regulatory subunit type I-? of protein kinase A (PRKAR1A): A tumor-suppressor gene for sporadic thyroid cancer

2002 ◽  
Vol 35 (2) ◽  
pp. 182-192 ◽  
Author(s):  
Fabiano Sandrini ◽  
Ludmila Matyakhina ◽  
Nicholas J. Sarlis ◽  
Lawrence S. Kirschner ◽  
Constantine Farmakidis ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Protein Kinase ◽  
Tumor Suppressor ◽  
Protein Kinase A ◽  
Tumor Suppressor Gene ◽  
Suppressor Gene ◽  
Regulatory Subunit ◽  
Type I ◽  
Kinase A

scholarly journals Mutations in the protein kinase A R1α regulatory subunit cause familial cardiac myxomas and Carney complex

2000 ◽  
Vol 106 (5) ◽  
pp. R31-R38 ◽  
Author(s):  
Mairead Casey ◽  
Carl J. Vaughan ◽  
Jie He ◽  
Cathy J. Hatcher ◽  
Jordan M. Winter ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Cardiac Myxomas ◽  
Kinase A

scholarly journals The regulatory 1α subunit of protein kinase A modulates renal cystogenesis

2017 ◽  
Vol 313 (3) ◽  
pp. F677-F686 ◽  
Author(s):  
Hong Ye ◽  
Xiaofang Wang ◽  
Megan M. Constans ◽  
Caroline R. Sussman ◽  
Fouad T. Chebib ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Signaling Pathways ◽  
Primary Cilia ◽  
Control Cell ◽  
Carney Complex ◽  
Regulatory Subunit ◽  
Renal Cystic Disease ◽  
Kinase A

The failure of the polycystins (PCs) to function in primary cilia is thought to be responsible for autosomal dominant polycystic kidney disease (ADPKD). Primary cilia integrate multiple cellular signaling pathways, including calcium, cAMP, Wnt, and Hedgehog, which control cell proliferation and differentiation. It has been proposed that mutated PCs result in reduced intracellular calcium, which in turn upregulates cAMP, protein kinase A (PKA) signaling, and subsequently other proliferative signaling pathways. However, the role of PKA in ADPKD has not been directly ascertained in vivo, although the expression of the main regulatory subunit of PKA in cilia and other compartments (PKA-RIα, encoded by PRKAR1A) is increased in a mouse model orthologous to ADPKD. Therefore, we generated a kidney-specific knockout of Prkar1a to examine the consequences of constitutive upregulation of PKA on wild-type and Pkd1 hypomorphic ( Pkd1RC) backgrounds. Kidney-specific loss of Prkar1a induced renal cystic disease and markedly aggravated cystogenesis in the Pkd1RC models. In both settings, it was accompanied by upregulation of Src, Ras, MAPK/ERK, mTOR, CREB, STAT3, Pax2 and Wnt signaling. On the other hand, Gli3 repressor activity was enhanced, possibly contributing to hydronephrosis and impaired glomerulogenesis in some animals. To assess the relevance of these observations in humans we looked for and found evidence for kidney and liver cystic phenotypes in the Carney complex, a tumoral syndrome caused by mutations in PRKAR1A. These observations expand our understanding of the pathogenesis of ADPKD and demonstrate the importance of PRKAR1A highlighting PKA as a therapeutic target in ADPKD.

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.

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