PRKACA: the catalytic subunit of protein kinase A and adrenocortical tumors.

Annabel S Berthon,Eva Szarek,Constantine A Stratakis

doi:10.3389/fcell.2015.00026

Abstract

Cyclic-AMP (cAMP)-dependent protein kinase (PKA) is the main effector of cAMP signaling in all tissues. Inactivating mutations of the PRKAR1A gene, coding for the type 1A regulatory subunit of PKA, are responsible for Carney complex and primary pigmented nodular adrenocortical disease (PPNAD). PRKAR1A inactivation and PKA dysregulation have been implicated in various types of adrenocortical pathologies associated with ACTH-independent Cushing syndrome (AICS) from PPNAD to adrenocortical adenomas and cancer, and other forms of bilateral adrenocortical hyperplasias (BAH). More recently, mutations of PRKACA, the gene coding for the catalytic subunit C alpha (Cα), were also identified in the pathogenesis of adrenocortical tumors. PRKACA copy number gain was found in the germline of several patients with cortisol-producing BAH, whereas the somatic Leu206Arg (c.617A>C) recurrent PRKACA mutation was found in as many as half of all adrenocortical adenomas associated with AICS. In vitro analysis demonstrated that this mutation led to constitutive Cα activity, unregulated by its main partners, the PKA regulatory subunits. In this review, we summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of PKA's role in adrenocortical lesions. We also discuss potential therapeutic advances that can be made through targeting of PRKACA and the PKA pathway.

Highlights

We summarize the current understanding of the involvement of PRKACA in adrenocortical tumorigenesis, and our understanding of protein kinase A (PKA)’s role in adrenocortical lesions
The adrenal cortex is divided into three concentric zones: the outermost zone named zona glomerulosa, the centrally located zona fasciculata and the innermost, zona reticularis involved in the production of mineralocorticoids, glucocorticoids, and androgens, respectively (Blake et al, 2008; Mcnicol, 2013)
In an initial cohort of 10 cortisol-producing adrenocortical adenomas (ACA) associated with overt ACTH-independent Cushing syndrome (AICS), the Leu206Arg (c.617A>C) PRKACA recurrent mutation was identified in 70% of these cases; with one ACA having another PRKACA defect, Leu199_Cys200insTrp (Beuschlein et al, 2014)

Summary

Introduction

The adrenal cortex is divided into three concentric zones: the outermost zone named zona glomerulosa, the centrally located zona fasciculata and the innermost, zona reticularis involved in the production of mineralocorticoids, glucocorticoids, and androgens, respectively (Blake et al, 2008; Mcnicol, 2013). Unilateral ACTs, ACAs account for 90% of adrenal CS (Newell-Price et al, 2006; Bertagna et al, 2009) These tumors arise at any age, with a slight female predominance. In contrast to ACAs, ACCs are rare and account for few cases of adrenal CS (Wajchenberg et al, 2000) They arise sporadically, mostly around the fourth and fifth decade of life; ACCs typically weigh more than 100 g, tend to be adherent to other tissues, or invade adjacent structures. A number of in vitro and transgenic mouse studies have demonstrated that PRKAR1A is an adrenocortical tumor suppressor gene and its inactivation leads to ACTH-independent cortisol secretion (Sahut-Barnola et al, 2010; Almeida and Stratakis, 2011)

PRKACA Genetic Defects Lead to Tumors of the Adrenal Cortex

Adrenocortical oncocytoma

Findings

Conclusions