Human Gene PRKACA (ENST00000308677.9) from GENCODE V44
Description: Homo sapiens protein kinase cAMP-activated catalytic subunit alpha (PRKACA), transcript variant 1, mRNA. (from RefSeq NM_002730) RefSeq Summary (NM_002730): This gene encodes one of the catalytic subunits of protein kinase A, which exists as a tetrameric holoenzyme with two regulatory subunits and two catalytic subunits, in its inactive form. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. Four different regulatory subunits and three catalytic subunits have been identified in humans. cAMP-dependent phosphorylation of proteins by protein kinase A is important to many cellular processes, including differentiation, proliferation, and apoptosis. Constitutive activation of this gene caused either by somatic mutations, or genomic duplications of regions that include this gene, have been associated with hyperplasias and adenomas of the adrenal cortex and are linked to corticotropin-independent Cushing's syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. Tissue-specific isoforms that differ at the N-terminus have been described, and these isoforms may differ in the post-translational modifications that occur at the N-terminus of some isoforms. [provided by RefSeq, Jan 2015]. Gencode Transcript: ENST00000308677.9 Gencode Gene: ENSG00000072062.16 Transcript (Including UTRs) Position: hg38 chr19:14,091,688-14,117,762 Size: 26,075 Total Exon Count: 10 Strand: - Coding Region Position: hg38 chr19:14,093,112-14,117,547 Size: 24,436 Coding Exon Count: 10
ID:KAPCA_HUMAN DESCRIPTION: RecName: Full=cAMP-dependent protein kinase catalytic subunit alpha; Short=PKA C-alpha; EC=2.7.11.11; FUNCTION: Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B- alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha- difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Prevents meiosis redumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein. ENZYME REGULATION: Allosterically activated by various compounds, including ATP. Activated by cAMP; the nucleotide acts as a dynamic and allosteric activator by coupling the two lobes of apo PKA, enhancing the enzyme dynamics synchronously and priming it for catalysis. Inhibited by H89 (N-[2-[[3-(4-Bromophenyl)-2- propenyl]amino]ethyl]-5-isoquinolinesulfonamide), spiroindoline, azole-based inhibitors, (3s)-amino-aminomethylbenzamide analogs, ARC-1032 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxyoxolan-2-yl]formamido}-N-[(1R)-4-carbamimidamido-1- carbamoylbutyl]hexanamide), ARC-1034 (6-{[(2S,3S,4R,5R)-5-(6- amino-9H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]formamido}-N-[(1R)- 4-carbamimidamido-1-{[(1R)-4-carbamimidamido-1- carbamoylbutyl]carbamoyl}butyl]hexanamide), ARC-582, ARC-902 (Adc- 6-aminohexanoic acid-(D-Arg)(6)-NH(2)), ARC-1012 ((2R)-6-amino-2- (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxyoxolan- 2-yl]formamido}hexanamido)-N-(5-{[(1R)-4-carbamimidamido-1-{[(1R)- 4-carbamimidamido-1- carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)hexanamide) and ARC-1039 (6-{[(2S,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4- dihydroxyoxolan-2-yl]formamido}-N-[(1R)-1-[(5-{[(1R)-4- carbamimidamido-1-{[(1R)-4-carbamimidamido-1- carbamoylbutyl]carbamoyl}butyl]carbamoyl}pentyl)carbamoyl]ethyl]he xanamide). SUBUNIT: A number of inactive tetrameric holoenzymes are produced by the combination of homo- or heterodimers of the different regulatory subunits associated with two catalytic subunits. cAMP causes the dissociation of the inactive holoenzyme into a dimer of regulatory subunits bound to four cAMP and two free monomeric catalytic subunits. The cAMP-dependent protein kinase catalytic subunit binds PJA2. Both isoforms 1 and 2 forms activate cAMP- sensitive PKAI and PKAII holoenzymes by interacting with regulatory subunit (R) of PKA, PRKAR1A/PKR1 and PRKAR2A/PKR2, respectively. Interacts with NFKB1, NFKB2 and NFKBIA in platlets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. INTERACTION: Q9NQ31:AKIP1; NbExp=4; IntAct=EBI-476586, EBI-517035; SUBCELLULAR LOCATION: Cytoplasm. Cell membrane. Nucleus (By similarity). Mitochondrion (By similarity). Note=Translocates into the nucleus (monomeric catalytic subunit). The inactive holoenzyme is found in the cytoplasm. Distributed throughout the cytoplasm in meiotically incompetent oocytes. Associated to mitochondrion as meiotic competence is acquired. Aggregates around the germinal vesicles (GV) at the immature GV stage oocytes (By similarity). TISSUE SPECIFICITY: Isoform 1 is ubiquitous. Isoform 2 is sperm specific. PTM: Asn-3 is partially deaminated to Asp giving rise to 2 major isoelectric variants, called CB and CA respectively (By similarity). PTM: Autophosphorylated. Phosphorylation is enhanced by vitamin K(2). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity. SIMILARITY: Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. SIMILARITY: Contains 1 AGC-kinase C-terminal domain. SIMILARITY: Contains 1 protein kinase domain. WEB RESOURCE: Name=SeattleSNPs; URL="http://pga.gs.washington.edu/data/prkaca/";
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on P17612
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.
Biological Process: GO:0000086 G2/M transition of mitotic cell cycle GO:0001707 mesoderm formation GO:0001843 neural tube closure GO:0002027 regulation of heart rate GO:0002223 stimulatory C-type lectin receptor signaling pathway GO:0003091 renal water homeostasis GO:0006397 mRNA processing GO:0006468 protein phosphorylation GO:0007596 blood coagulation GO:0010389 regulation of G2/M transition of mitotic cell cycle GO:0010881 regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion GO:0016241 regulation of macroautophagy GO:0016310 phosphorylation GO:0018105 peptidyl-serine phosphorylation GO:0018107 peptidyl-threonine phosphorylation GO:0019221 cytokine-mediated signaling pathway GO:0034199 activation of protein kinase A activity GO:0034380 high-density lipoprotein particle assembly GO:0034605 cellular response to heat GO:0035584 calcium-mediated signaling using intracellular calcium source GO:0043393 regulation of protein binding GO:0045667 regulation of osteoblast differentiation GO:0046777 protein autophosphorylation GO:0046827 positive regulation of protein export from nucleus GO:0048240 sperm capacitation GO:0050804 modulation of synaptic transmission GO:0051480 regulation of cytosolic calcium ion concentration GO:0055117 regulation of cardiac muscle contraction GO:0060314 regulation of ryanodine-sensitive calcium-release channel activity GO:0061136 regulation of proteasomal protein catabolic process GO:0070613 regulation of protein processing GO:0071158 positive regulation of cell cycle arrest GO:0071333 cellular response to glucose stimulus GO:0071374 cellular response to parathyroid hormone stimulus GO:0071377 cellular response to glucagon stimulus GO:0071872 cellular response to epinephrine stimulus GO:0086064 cell communication by electrical coupling involved in cardiac conduction GO:0097711 ciliary basal body docking GO:1901621 negative regulation of smoothened signaling pathway involved in dorsal/ventral neural tube patterning GO:1903779 regulation of cardiac conduction GO:2000810 regulation of bicellular tight junction assembly
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