Target General Infomation
Target ID
T20669
Former ID
TTDR01375
Target Name
mRNA of PKA Catalytic Subunit C-alpha
Gene Name
PRKACA
Synonyms
PKA Calpha (mRNA); PRKACA (mRNA); cAMPdependent protein kinase catalytic subunit alpha (mRNA); PRKACA
Target Type
Discontinued
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 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.
BioChemical Class
Kinase
Target Validation
T20669
UniProt ID
EC Number
EC 2.7.11.11
Sequence
MGNAAAAKKGSEQESVKEFLAKAKEDFLKKWESPAQNTAHLDQFERIKTLGTGSFGRVML
VKHKETGNHYAMKILDKQKVVKLKQIEHTLNEKRILQAVNFPFLVKLEFSFKDNSNLYMV
MEYVPGGEMFSHLRRIGRFSEPHARFYAAQIVLTFEYLHSLDLIYRDLKPENLLIDQQGY
IQVTDFGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALGVLIYEMAAGYPPFF
ADQPIQIYEKIVSGKVRFPSHFSSDLKDLLRNLLQVDLTKRFGNLKNGVNDIKNHKWFAT
TDWIAIYQRKVEAPFIPKFKGPGDTSNFDDYEEEEIRVSINEKCGKEFSEF
Drugs and Mode of Action
Drug(s) BALANOL Drug Info Terminated Discovery agent [542983], [545589]
Inhibitor 4-[(3,5-diamino-1H-pyrazol-4-yl)diazenyl]phenol Drug Info [528490]
BALANOL Drug Info [527710]
H-89 Drug Info [531474]
NM-PP1 Drug Info [529039]
Ro-4396686 Drug Info [528018]
Pathways
KEGG Pathway MAPK signaling pathway
Ras signaling pathway
Calcium signaling pathway
cAMP signaling pathway
Chemokine signaling pathway
Oocyte meiosis
Apoptosis
Adrenergic signaling in cardiomyocytes
Vascular smooth muscle contraction
Wnt signaling pathway
Hedgehog signaling pathway
Gap junction
Platelet activation
Circadian entrainment
Long-term potentiation
Retrograde endocannabinoid signaling
Glutamatergic synapse
Cholinergic synapse
Serotonergic synapse
GABAergic synapse
Dopaminergic synapse
Olfactory transduction
Taste transduction
Inflammatory mediator regulation of TRP channels
Insulin signaling pathway
Insulin secretion
GnRH signaling pathway
Ovarian steroidogenesis
Progesterone-mediated oocyte maturation
Estrogen signaling pathway
Melanogenesis
Thyroid hormone synthesis
Thyroid hormone signaling pathway
Oxytocin signaling pathway
Glucagon signaling pathway
Regulation of lipolysis in adipocytes
Renin secretion
Endocrine and other factor-regulated calcium reabsorption
Vasopressin-regulated water reabsorption
Salivary secretion
Gastric acid secretion
Bile secretion
Parkinson&#039
s disease
Prion diseases
Cocaine addiction
Amphetamine addiction
Morphine addiction
Alcoholism
Vibrio cholerae infection
Amoebiasis
HTLV-I infection
Epstein-Barr virus infection
Pathways in cancer
Viral carcinogenesis
Proteoglycans in cancer
Dilated cardiomyopathy
PANTHER Pathway Endothelin signaling pathway
Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway
Heterotrimeric G-protein signaling pathway-rod outer segment phototransduction
Inflammation mediated by chemokine and cytokine signaling pathway
Metabotropic glutamate receptor group III pathway
Metabotropic glutamate receptor group II pathway
Metabotropic glutamate receptor group I pathway
Muscarinic acetylcholine receptor 2 and 4 signaling pathway
5HT1 type receptor mediated signaling pathway
Beta1 adrenergic receptor signaling pathway
Beta2 adrenergic receptor signaling pathway
Histamine H2 receptor mediated signaling pathway
GABA-B receptor II signaling
Dopamine receptor mediated signaling pathway
Enkephalin release
Nicotine pharmacodynamics pathway
CCKR signaling map ST
Pathway Interaction Database GMCSF-mediated signaling events
LPA4-mediated signaling events
Signaling events regulated by Ret tyrosine kinase
LKB1 signaling events
Thromboxane A2 receptor signaling
SHP2 signaling
Signaling events mediated by HDAC Class I
Role of Calcineurin-dependent NFAT signaling in lymphocytes
Glucocorticoid receptor regulatory network
ErbB2/ErbB3 signaling events
IL3-mediated signaling events
Syndecan-1-mediated signaling events
Retinoic acid receptors-mediated signaling
Hedgehog signaling events mediated by Gli proteins
VEGFR1 specific signals
Calcium signaling in the CD4+ TCR pathway
Signaling events mediated by VEGFR1 and VEGFR2
Syndecan-2-mediated signaling events
Aurora A signaling
Class I PI3K signaling events mediated by Akt
Alpha4 beta1 integrin signaling events
PathWhiz Pathway Muscle/Heart Contraction
Reactome Hormone-sensitive lipase (HSL)-mediated triacylglycerol hydrolysis
PKA activation
PKA activation in glucagon signalling
DARPP-32 events
Regulation of PLK1 Activity at G2/M Transition
Loss of Nlp from mitotic centrosomes
Recruitment of mitotic centrosome proteins and complexes
Loss of proteins required for interphase microtubule organization?from the centrosome
Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
Regulation of insulin secretion
Vasopressin regulates renal water homeostasis via Aquaporins
VEGFA-VEGFR2 Pathway
Interleukin-3, 5 and GM-CSF signaling
Degradation of GLI1 by the proteasome
Degradation of GLI2 by the proteasome
Hedgehog &#039
off&#039
state
Anchoring of the basal body to the plasma membrane
CD209 (DC-SIGN) signaling
MAPK6/MAPK4 signaling
Gluconeogenesis
Factors involved in megakaryocyte development and platelet production
WikiPathways SIDS Susceptibility Pathways
Hypothetical Network for Drug Addiction
Calcium Regulation in the Cardiac Cell
Endochondral Ossification
MAPK Signaling Pathway
G Protein Signaling Pathways
Myometrial Relaxation and Contraction Pathways
IL-3 Signaling Pathway
Mesodermal Commitment Pathway
Human Complement System
DAG and IP3 signaling
Regulation of Water Balance by Renal Aquaporins
Dopamine metabolism
Regulation of Microtubule Cytoskeleton
FSH signaling pathway
miRs in Muscle Cell Differentiation
SREBP signalling
Opioid Signalling
Mitotic G2-G2/M phases
Integration of energy metabolism
Factors involved in megakaryocyte development and platelet production
Nicotine Activity on Dopaminergic Neurons
References
Ref 542983(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 8142).
Ref 545589Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003814)
Ref 527710J Med Chem. 2005 Sep 8;48(18):5613-38.Joys of molecules. 2. Endeavors in chemical biology and medicinal chemistry.
Ref 528018Bioorg Med Chem Lett. 2006 Apr 1;16(7):1950-3. Epub 2006 Feb 3.Biological evaluation of a multi-targeted small molecule inhibitor of tumor-induced angiogenesis.
Ref 528490J Med Chem. 2006 Nov 2;49(22):6500-9.4-arylazo-3,5-diamino-1H-pyrazole CDK inhibitors: SAR study, crystal structure in complex with CDK2, selectivity, and cellular effects.
Ref 529039Biochem J. 2007 Dec 15;408(3):297-315.The selectivity of protein kinase inhibitors: a further update.
Ref 531474Inhibition of forskolin-induced neurite outgrowth and protein phosphorylation by a newly synthesized selective inhibitor of cyclic AMP-dependent protein kinase, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), of PC12D pheochromocytoma cells. J Biol Chem. 1990 Mar 25;265(9):5267-72.
Ref 549631US patent application no. 6,248,586, Antisense modulation of PKA catalytic subunit C-alpha expression.

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