# PRKACA

## Overview
The PRKACA gene encodes the protein kinase cAMP-activated catalytic subunit alpha, a critical component of the protein kinase A (PKA) enzyme, which is a serine/threonine kinase. This kinase plays a pivotal role in cellular signaling pathways by phosphorylating a wide array of target proteins, thereby regulating numerous physiological processes such as glucose metabolism, cell division, and synaptic transmission. The PRKACA protein is characterized by a conserved kinase domain essential for its enzymatic activity and a bilobal structure that facilitates nucleotide and substrate binding (Turnham2016Protein; Knighton1991Crystal). The gene's expression and function are tightly regulated, with alterations in its activity linked to various diseases, including Cushing's syndrome and certain cancers (Stratakis2014E; Di2014Novel). The protein's interactions with A-kinase anchoring proteins (AKAPs) further refine its signaling specificity, underscoring its importance in maintaining cellular homeostasis (Turnham2016Protein).

## Structure
The PRKACA gene encodes the catalytic subunit alpha of protein kinase A (PKA), a serine/threonine kinase involved in various cellular processes. The primary structure of PRKACA includes a conserved kinase domain, which is crucial for its enzymatic activity (Turnham2016Protein). The secondary structure of the protein features a bilobal architecture, with a smaller lobe primarily involved in nucleotide binding and a larger lobe associated with peptide binding and catalysis. This structure is characterized by a β-sheet in the smaller lobe and α-helices in the larger lobe (Knighton1991Crystal).

The tertiary structure of PRKACA forms a distinct kinase fold, with a deep cleft between the lobes where MgATP and substrate peptides bind. Key residues such as Lys72, Asp184, and Glu91 are involved in MgATP binding and catalysis, highlighting the importance of the conserved catalytic core (Knighton1991Crystal). The quaternary structure of PKA involves the formation of a holoenzyme, consisting of two regulatory and two catalytic subunits, which dissociate upon cAMP binding to activate the kinase (Turnham2016Protein).

PRKACA has several splice variant isoforms, including Cα1, Cα2, and Cα3, with Cα1 being the most ubiquitously expressed (Turnham2016Protein). Common post-translational modifications include phosphorylation, which is essential for its regulatory functions (Knighton1991Structure).

## Function
The PRKACA gene encodes the catalytic subunit alpha (Cα) of protein kinase A (PKA), a serine/threonine kinase that plays a crucial role in cellular signaling by phosphorylating various downstream targets. In its inactive form, PKA exists as a tetramer composed of two regulatory (R) subunits and two catalytic (C) subunits. Upon binding of cyclic AMP (cAMP) to the R subunits, the C subunits are released and become active, allowing them to phosphorylate target proteins. This process is essential for propagating cAMP-responsive cell signaling events, which regulate numerous cellular processes, including glucose metabolism, cell division, development, stress responses, and synaptic transmission (Turnham2016Protein).

The specificity of PKA signaling is enhanced by A-kinase anchoring proteins (AKAPs), which localize the PKA holoenzyme to specific subcellular locations, optimizing signal transduction. AKAPs can cluster PKA with other signaling enzymes, allowing cells to respond efficiently to second messenger signals (Turnham2016Protein). In healthy human cells, PRKACA is involved in various physiological processes, including synaptic transmission, glucose homeostasis, cardiac transcriptional regulation, and higher-order cognitive functions (Turnham2016Protein). The PRKACA protein is conserved across many organisms, and its deletion in mice leads to growth retardation and neural tube defects, indicating its essential role in development and cellular function (Turnham2016Protein).

## Clinical Significance
Mutations in the PRKACA gene, which encodes the catalytic subunit of protein kinase A (PKA), are implicated in several diseases, most notably Cushing's syndrome. This condition is characterized by excessive cortisol production, often due to adrenocortical adenomas. A recurrent mutation, c.617A>C (p.Leu206Arg), leads to constitutive activation of the PKA catalytic subunit, resulting in cAMP-independent activity and increased cortisol production. This mutation is found in a significant proportion of patients with Cushing's syndrome associated with adrenocortical adenomas (Sato2014Recurrent; Di2014Novel).

PRKACA mutations are also linked to bilateral adrenal hyperplasia and Carney Complex (CNC), a syndrome that includes multiple neoplasias. In CNC, germline amplification of PRKACA can lead to unregulated PKA activity, contributing to the development of conditions like primary pigmented nodular adrenocortical disease (PPNAD) and Cushing's syndrome (Yang2024Germline).

Alterations in PRKACA expression or its interactions can also contribute to tumorigenesis in other tissues, such as fibrolamellar hepatocellular carcinoma and potentially breast cancer, highlighting its role as a likely oncogene (Stratakis2014E). These findings underscore the importance of PRKACA in various pathologies related to dysregulated cAMP signaling.

## Interactions
PRKACA, the catalytic subunit of protein kinase A (PKA), participates in various interactions that regulate its activity and function. In its inactive form, PRKACA is part of the PKA holoenzyme, which consists of two regulatory (R) subunits and two catalytic subunits. Upon binding of cyclic AMP (cAMP) to the R subunits, the catalytic subunits, including PRKACA, are released to phosphorylate target proteins (Turnham2016Protein).

PRKACA interacts with A-kinase anchoring proteins (AKAPs), which play a crucial role in targeting the PKA holoenzyme to specific subcellular locations. This interaction allows for localized cAMP-responsive events and the formation of macromolecular complexes that include other signaling enzymes, such as protein kinase C (PKC) and protein phosphatases (Turnham2016Protein).

In the context of cancer, PRKACA's interactions are altered. For instance, in colorectal cancer, lysine crotonylation of PRKACA at K84 affects its interaction with the regulatory subunit PRKAR1A, leading to increased PKA activity and promoting cancer cell proliferation, migration, and invasion (Hou2023Crotonylation). In fibrolamellar hepatocellular carcinoma, the DNAJB1-PRKACA fusion protein interacts with β-catenin, enhancing tumorigenesis through the Wnt signaling pathway (Kastenhuber2017DNAJB1–PRKACA).


## References


[1. (Sato2014Recurrent) Yusuke Sato, Shigekatsu Maekawa, Ryohei Ishii, Masashi Sanada, Teppei Morikawa, Yuichi Shiraishi, Kenichi Yoshida, Yasunobu Nagata, Aiko Sato-Otsubo, Tetsuichi Yoshizato, Hiromichi Suzuki, Yusuke Shiozawa, Keisuke Kataoka, Ayana Kon, Kosuke Aoki, Kenichi Chiba, Hiroko Tanaka, Haruki Kume, Satoru Miyano, Masashi Fukayama, Osamu Nureki, Yukio Homma, and Seishi Ogawa. Recurrent somatic mutations underlie corticotropin-independent cushing’s syndrome. Science, 344(6186):917–920, May 2014. URL: http://dx.doi.org/10.1126/science.1252328, doi:10.1126/science.1252328. This article has 167 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.1252328)

[2. (Stratakis2014E) Constantine A. Stratakis. E pluribus unum? the main protein kinase a catalytic subunit (prkaca), a likely oncogene, and cortisol-producing tumors. The Journal of Clinical Endocrinology & Metabolism, 99(10):3629–3633, October 2014. URL: http://dx.doi.org/10.1210/jc.2014-3295, doi:10.1210/jc.2014-3295. This article has 23 citations.](https://doi.org/10.1210/jc.2014-3295)

[3. (Kastenhuber2017DNAJB1–PRKACA) Edward R. Kastenhuber, Gadi Lalazar, Shauna L. Houlihan, Darjus F. Tschaharganeh, Timour Baslan, Chi-Chao Chen, David Requena, Sha Tian, Benedikt Bosbach, John E. Wilkinson, Sanford M. Simon, and Scott W. Lowe. Dnajb1–prkaca fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma. Proceedings of the National Academy of Sciences, 114(50):13076–13084, November 2017. URL: http://dx.doi.org/10.1073/pnas.1716483114, doi:10.1073/pnas.1716483114. This article has 122 citations.](https://doi.org/10.1073/pnas.1716483114)

[4. (Turnham2016Protein) Rigney E. Turnham and John D. Scott. Protein kinase a catalytic subunit isoform prkaca; history, function and physiology. Gene, 577(2):101–108, February 2016. URL: http://dx.doi.org/10.1016/j.gene.2015.11.052, doi:10.1016/j.gene.2015.11.052. This article has 143 citations and is from a peer-reviewed journal.](https://doi.org/10.1016/j.gene.2015.11.052)

[5. (Knighton1991Crystal) Daniel R. Knighton, Jianhua Zheng, Lynn F. Ten Eyck, Victor A. Ashford, Nguyen-Huu Xuong, Susan S. Taylor, and Janusz M. Sowadski. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science, 253(5018):407–414, July 1991. URL: http://dx.doi.org/10.1126/science.1862342, doi:10.1126/science.1862342. This article has 1382 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.1862342)

[6. (Di2014Novel) Guido Di Dalmazi, Caroline Kisker, Davide Calebiro, Massimo Mannelli, Letizia Canu, Giorgio Arnaldi, Marcus Quinkler, Nada Rayes, Antoine Tabarin, Marie Laure Jullié, Franco Mantero, Beatrice Rubin, Jens Waldmann, Detlef K. Bartsch, Renato Pasquali, Martin Lohse, Bruno Allolio, Martin Fassnacht, Felix Beuschlein, and Martin Reincke. Novel somatic mutations in the catalytic subunit of the protein kinase a as a cause of adrenal cushing’s syndrome: a european multicentric study. The Journal of Clinical Endocrinology & Metabolism, 99(10):E2093–E2100, October 2014. URL: http://dx.doi.org/10.1210/jc.2014-2152, doi:10.1210/jc.2014-2152. This article has 89 citations.](https://doi.org/10.1210/jc.2014-2152)

[7. (Knighton1991Structure) Daniel R. Knighton, Jianhua Zheng, Lynn F. Ten Eyck, Nguyen-huu Xuong, Susan S. Taylor, and Janusz M. Sowadski. Structure of a peptide inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science, 253(5018):414–420, July 1991. URL: http://dx.doi.org/10.1126/science.1862343, doi:10.1126/science.1862343. This article has 769 citations and is from a highest quality peer-reviewed journal.](https://doi.org/10.1126/science.1862343)

[8. (Hou2023Crotonylation) Jia-Yi Hou, Li-Juan Gao, Jing Shen, Lan Zhou, Jian-Yun Shi, Teng Sun, Shu-Lan Hao, De-Ping Wang, and Ji-Min Cao. Crotonylation of prkaca enhances pka activity and promotes colorectal cancer development via the pka-fak-akt pathway. Genes & Diseases, 10(2):332–335, March 2023. URL: http://dx.doi.org/10.1016/j.gendis.2022.02.018, doi:10.1016/j.gendis.2022.02.018. This article has 3 citations.](https://doi.org/10.1016/j.gendis.2022.02.018)

[9. (Yang2024Germline) Wang-Rong Yang, Xing-Huan Liang, Ying-Fen Qin, Hai-Yan Yang, Shu-Zhan He, Zhen-Xing Huang, Yu-Ping Liu, and Zuo-Jie Luo. Germline prkaca amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review. Archives of Endocrinology and Metabolism, 2024. URL: http://dx.doi.org/10.20945/2359-4292-2022-0491, doi:10.20945/2359-4292-2022-0491. This article has 1 citations.](https://doi.org/10.20945/2359-4292-2022-0491)