Thecatalytic subunit α of protein kinase A is a key regulatoryenzyme that in humans is encoded by thePRKACAgene.[5] This enzyme is responsible forphosphorylating other proteins and substrates, changing their activity.Protein kinase A catalytic subunit (PKA Cα) is a member of theAGC kinase family (protein kinases A,G, andC), and contributes to the control of cellular processes that includeglucose metabolism,cell division, and contextual memory.[6][7][8] PKA Cα is part of a larger protein complex that is responsible for controlling when and where proteins are phosphorylated. Defective regulation of PKAholoenzyme activity has been linked to the progression of cardiovascular disease, certain endocrine disorders and cancers.
Edmond H. Fischer andEdwin G. Krebs at the University of Washington discovered PKA in the late 1950s while working through the mechanisms that governglycogen phosphorylase. They realized that a key metabolic enzyme called phosphorylase kinase was activated by another kinase that was dependent on the second messengercyclic AMP (cAMP).[9] They named this new enzyme the cAMP-dependent protein kinase, and proceeded to purify and characterize this new enzyme. Fischer and Krebs won the Nobel Prize in Physiology or Medicine in 1992 for this discovery and their continued work on kinases, and their counterparts the proteinphosphatases. Today, this cAMP-dependent protein kinase is more simply noted as PKA.
Another key event in the history of PKA occurred when Susan Taylor and Janusz Sowadski at theUniversity of California San Diego solved the three dimensional structure of the catalytic subunit of the enzyme.[10] It was also realized that inside cells, PKA catalytic subunits are found in complex with regulatory subunits and inhibitor proteins that block the activity of the enzyme. An additional facet of PKA action that was pioneered by John Scott at theUniversity of Washington and Kjetil Tasken at theUniversity of Oslo is that the enzyme is tethered within the cell through its association with a family ofA-kinase-anchoring proteins (AKAPs). This led to the hypothesis that thesubcellular localization of anchored PKA controls what proteins are regulated by the kinase.[11]
PRKACA is found onchromosome 19 in humans.[5] There are two well-described transcripts of this gene, arising fromalternative splicing events. The most common form, called Cα1, is expressed throughout human tissue. Another transcript, called Cα2, is found primarily insperm cells and differs from Cα1 only in the first 15amino acids.[12]
In addition, there are two other isoforms of the catalytic subunit of PKA called Cβ and Cγ arising from different genes but have similar functions as Cα.[13][14] Cβ is found abundantly in the brain and in lower levels in other tissues, while Cγ is most likely expressed in the testis.
Inactive PKA holoenzyme exists as atetramer composed of two regulatory (R) subunits and two catalytic (C) subunits.[15] Biochemical studies demonstrated that there are two types of R subunits. The type I R subunits of which there are two isoforms (RIα, and RIβ) bind the catalytic subunits to create the type I PKA holoenzyme. Likewise type II R subunits, of which there are two isoforms (RIIα, and RIIβ), create the type II PKA holoenzyme. In the presence of cAMP, each R subunit binds 2 cAMP molecules and causes a conformational change in the R subunits that releases the C subunits to phosphorylate downstream substrates.[16] The different R subunits differ in their sensitivity to cAMP, expression levels and subcellular locations. A-kinase-anchoring proteins (AKAPs) bind a surface formed between both R subunits and target the kinase to different locations in the cell. This optimizes where and when cellular communication occurs within the cell.[11]
Protein kinase A has been implicated in a number of diseases, including cardiovascular disease, tumors of theadrenal cortex, and cancer. It has been speculated that abnormally high levels of PKA phosphorylation contributes to heart disease. This affects excitation-contraction coupling, which is a rhythmic process that controls the contraction of cardiac muscle through the synchronized actions ofcalcium andcAMP responsive enzymes.[17] There is also evidence to support that the mis-localization of PKA signaling contributes to cardiacarrhythmias, specificallyLong QT syndrome. This results in irregular heartbeats that can cause sudden death.
Mutations in thePRKACA gene that promote abnormal enzyme activity have been linked to disease of the adrenal gland. Several mutations inPRKACA have been found in patients withCushing's syndrome that result in an increase in the ability of PKA to broadly phosphorylate other proteins. One mutation in thePRKACA gene that causes an amino acid substitution ofleucine toarginine in position 206, was found in over 60% of patients withadrenocortical tumors.[18] Other mutations and genetic alterations in thePRKACA gene have been identified inadrenocortical adenomas that also disrupt PKA signaling, leading to aberrant PKA phosphorylation. The Cα gene has also been incriminated in a variety of cancers, including colon, renal, rectal, prostate, lung, breast, adrenal carcinomas and lymphomas.
There is recent and growing interest infibrolamellar hepatocellular carcinoma. The molecular basis for this rare form of liver cancer that afflicts young adults is a genetic deletion on chromosome 19. The loss of DNA has been found in a very high percent of patients.[19] The consequence of this deletion is the abnormalfusion of two genes-DNAJB1, which is the gene that codes for theheat shock protein 40 (Hsp40), andPRKACA. Further analyses of fibrolamellar hepatocellular carcinoma tissues show an increase in protein levels of this DNAJ-PKAc fusion protein. This is consistent with the hypothesis that increased kinase in liver tissues can initiate or perpetuate this rare form of liver cancer. Given the wealth of information on the three dimensional structures of DNAJ and PKA Cα there is some hope that new drugs can be developed to target this atypical and potentially tumorigenic fusion kinase.
 | The 2015 version of this article was updated by an external expert under a dual publication model. The correspondingacademic peer reviewed article was published inGene and can be cited as: Rigney E Turnham; John D Scott (11 December 2015)."Protein kinase A catalytic subunit isoform PRKACA; History, function and physiology".Gene. Gene Wiki Review Series.577 (2):101–108.doi:10.1016/J.GENE.2015.11.052.ISSN 0378-1119.PMC 4713328.PMID 26687711.Wikidata Q34505964. |
