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MGP002414

UniProt Annotations

Entry Information
Gene Nameprotein kinase, cAMP-dependent, catalytic, alpha
Protein Entry
UniProt ID
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; Synonyms=C-alpha-1; IsoId=P17612-1; Sequence=Displayed; Name=2; Synonyms=C-alpha-2, C-alpha-S, C(s); IsoId=P17612-2; Sequence=VSP_004759;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein.
DiseasePrimary pigmented nodular adrenocortical disease 4 (PPNAD4) [MIM:615830]: A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24571724, ECO:0000269|PubMed:24700472, ECO:0000269|PubMed:24747643, ECO:0000269|PubMed:24855271}. Note=The disease is caused by mutations affecting the gene represented in this entry.
Enzyme RegulationAllosterically 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). {ECO:0000269|PubMed:17909264, ECO:0000269|PubMed:18178622, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20137943, ECO:0000269|PubMed:20481595, ECO:0000269|PubMed:20732331}.
FunctionPhosphorylates 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 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+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (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. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT). Phosphorylates APOBEC3G and AICDA. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. {ECO:0000269|PubMed:15642694, ECO:0000269|PubMed:15905176, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:17333334, ECO:0000269|PubMed:17565987, ECO:0000269|PubMed:17693412, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:19949837, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:21423175, ECO:0000269|PubMed:21514275, ECO:0000269|PubMed:21812984}.
InteractionQ9NQ31:AKIP1; NbExp=4; IntAct=EBI-476586, EBI-517035; P09917:ALOX5; NbExp=2; IntAct=EBI-476586, EBI-79934; P49841:GSK3B; NbExp=5; IntAct=EBI-476586, EBI-373586; Q5S007:LRRK2; NbExp=6; IntAct=EBI-476586, EBI-5323863; P10644:PRKAR1A; NbExp=2; IntAct=EBI-476586, EBI-476431; P12369:Prkar2b (xeno); NbExp=2; IntAct=EBI-476586, EBI-6096160;
PtmAsn-3 is partially deaminated to Asp giving rise to 2 major isoelectric variants, called CB and CA respectively. {ECO:0000250}.
PtmAutophosphorylated. Phosphorylation is enhanced by vitamin K(2). Phosphorylated on threonine and serine residues. Phosphorylation on Thr-198 is required for full activity. {ECO:0000269|PubMed:12372837, ECO:0000269|PubMed:16765046, ECO:0000269|PubMed:17909264, ECO:0000269|PubMed:18691976, ECO:0000269|PubMed:19690332, ECO:0000269|PubMed:20137943, ECO:0000269|PubMed:20481595, ECO:0000269|PubMed:20732331, ECO:0000269|PubMed:21774789, ECO:0000269|Ref.36}.
PtmPhosphorylated at Tyr-331 by activated receptor tyrosine kinases EGFR and PDGFR; this increases catalytic efficienncy. {ECO:0000250}.
SimilarityBelongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. cAMP subfamily. {ECO:0000305}.
SimilarityContains 1 AGC-kinase C-terminal domain. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm. Cell membrane. Nucleus {ECO:0000250}. Mitochondrion {ECO:0000250}. 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). {ECO:0000250}.
Subcellular LocationIsoform 2: Cell projection, cilium, flagellum. Note=Expressed in the midpiece region of the sperm flagellum.
SubunitA 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 platelets; these interactions are disrupted by thrombin and collagen. Binds to ABL1 in spermatozoa and with CDC25B in oocytes. Interacts with APOBEC3G and AICDA. Interacts with RAB13; downstream effector of RAB13 involved in tight junction assembly. {ECO:0000269|PubMed:15096524, ECO:0000269|PubMed:16387847, ECO:0000269|PubMed:18836454, ECO:0000269|PubMed:20356841, ECO:0000269|PubMed:20732331, ECO:0000269|PubMed:21774789, ECO:0000269|PubMed:21812984}.
Tissue SpecificityIsoform 1 is ubiquitous. Isoform 2 is sperm- specific and is enriched in pachytene spermatocytes but is not detected in round spermatids. {ECO:0000269|PubMed:10906071, ECO:0000269|PubMed:21812984}.
Web ResourceName=SeattleSNPs; URL="http://pga.gs.washington.edu/data/prkaca/";
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