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Editorial
. 2014 Oct;99(10):3629-33.
doi: 10.1210/jc.2014-3295.

E pluribus unum? The main protein kinase A catalytic subunit (PRKACA), a likely oncogene, and cortisol-producing tumors

Constantine A Stratakis  1
Affiliations
Editorial

E pluribus unum? The main protein kinase A catalytic subunit (PRKACA), a likely oncogene, and cortisol-producing tumors

Constantine A Stratakis. J Clin Endocrinol Metab. 2014 Oct.

Erratum in

  • Corrigenda.
    [No authors listed] [No authors listed] J Clin Endocrinol Metab. 2015 Feb;100(2):764. doi: 10.1210/jc.2014-4426. J Clin Endocrinol Metab. 2015. PMID: 25658155 Free PMC article. No abstract available.
No abstract available

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Figures

Figure 1.
Figure 1.
The involvement of cAMP signaling defects in CS is shown on this diagram. GPCRs that act through GNAS1 (Gsα), in response to a ligand hormone, activate adenylate cyclase to produce cAMP. cAMP mediates most of its effects through the cAMP-dependent PKA. PKA is a tetramer that consists of two inactive catalytic subunits and two regulatory subunits. The main regulatory subunit of PKA is PRKAR1A, and its main catalytic subunit is PRKACA; in the inactive tetramer, each catalytic subunit molecule is bound by a molecule of regulatory subunit. The two heterodimers are held together by the two inactive regulatory subunits. When two molecules of cAMP bind to each regulatory subunit, the tetramer dissolves, and the catalytic subunits are free to phosphorylate downstream targets. cAMP levels are regulated by PDEs. PDE11A and PDE8B mutations predispose to all types of cortisol-producing lesions of the adrenal cortex. Ectopic overexpression of GPCRs lead to macronodular forms of hyperplasia, whereas GNAS1 and PRKAR1A mutations lead to nodular and micronodular BAHs, respectively (A), and rarely to CPAs (C). Mutations of PRKAR1A also lead to Carney complex (B). PRKACA mutations lead to CPAs (C). Finally, there are a number of cortisol-producing lesions that are caused by yet unidentified genetic defects; three examples of such lesions from respective patients (two children and one adult with CS) are shown in panel D.
Figure 2.
Figure 2.
Increasing PRKACA activity in the adrenal cortex is associated with various types of histopathology and CS. PRKACA causes rare forms of BAH leading to CS in children and young adults when it is present as a germline defect associated with copy number gain of chromosome 19p13.12 material. It causes the relatively common CPA leading to CS in older age when it acquires mutations in the somatic state. The effect of dosage of PKA catalytic activity on the adrenal cortex requires testing in animal models, although it would be hard to translate findings to the human adrenal gland. It is likely that the Leu206Arg PRKACA mutation (and the other activating mutations identified so far) is not compatible with life in human embryos, which may explain why they are only found in the somatic state in CPAs.
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Comment on

References

    1. Stratakis CA, Kirschner LS. Clinical and genetic analysis of primary bilateral adrenal diseases (micro- and macronodular disease) leading to Cushing syndrome. Horm Metab Res. 1998;30:456–463 - PubMed
    1. Stratakis CA. cAMP/PKA signaling defects in tumors: genetics and tissue-specific pluripotential cell-derived lesions in human and mouse. Mol Cell Endocrinol. 2013;371:208–220 - PMC - PubMed
    1. Carney JA, Young WF, Stratakis CA. Primary bimorphic adrenocortical disease: cause of hypercortisolism in McCune-Albright syndrome. Am J Surg Pathol. 2011;35:1311–1326 - PMC - PubMed
    1. Lacroix A. Heredity and cortisol regulation in bilateral macronodular adrenal hyperplasia. N Engl J Med. 2013;369:2147–2149 - PubMed
    1. De Venanzi A, Alencar GA, Bourdeau I, Fragoso MC, Lacroix A. Primary bilateral macronodular adrenal hyperplasia. Curr Opin Endocrinol Diabetes Obes. 2014;21:177–184 - PubMed

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