Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAKDCMR)

• DOT Name: cAMP-dependent protein kinase catalytic subunit alpha (PRKACA)
• Synonyms: PKA C-alpha; EC 2.7.11.11
• Gene Name: PRKACA
• Related Disease:
  Cardioacrofacial dysplasia 1
  Pigmented nodular adrenocortical disease, primary, 4
• UniProt ID: KAPCA_HUMAN
• PDB ID: 2GU8 ; 3AGL ; 3AGM ; 3AMA ; 3AMB ; 3L9L ; 3L9M ; 3L9N ; 3MVJ ; 3NX8 ; 3OOG ; 3OVV ; 3OWP ; 3OXT ; 3P0M ; 3POO ; 3VQH ; 4AE6 ; 4AE9 ; 4UJ1 ; 4UJ2 ; 4UJ9 ; 4UJA ; 4UJB ; 4WB5 ; 4WB6 ; 4WB7 ; 4WB8 ; 5BX6 ; 5BX7 ; 5IZF ; 5IZJ ; 5J5X ; 5N23 ; 5UZK ; 6BYR ; 6BYS ; 6C0U ; 6FRX ; 6NO7 ; 6QJ7 ; 6WJF ; 6WJG ; 7Y1G ; 8FE2 ; 8FE5 ; 8FEC
• EC Number: 2.7.11.11
• Pfam ID: PF00069
• Sequence:
  MGNAAAAKKGSEQESVKEFLAKAKEDFLKKWESPAQNTAHLDQFERIKTLGTGSFGRVML
  VKHKETGNHYAMKILDKQKVVKLKQIEHTLNEKRILQAVNFPFLVKLEFSFKDNSNLYMV
  MEYVPGGEMFSHLRRIGRFSEPHARFYAAQIVLTFEYLHSLDLIYRDLKPENLLIDQQGY
  IQVTDFGFAKRVKGRTWTLCGTPEYLAPEIILSKGYNKAVDWWALGVLIYEMAAGYPPFF
  ADQPIQIYEKIVSGKVRFPSHFSSDLKDLLRNLLQVDLTKRFGNLKNGVNDIKNHKWFAT
  TDWIAIYQRKVEAPFIPKFKGPGDTSNFDDYEEEEIRVSINEKCGKEFSEF
• Function: Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, SOX9 and VASP. 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. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in chondrogenesis by mediating phosphorylation of SOX9. 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. Required for phosphorylation of GLI transcription factors which inhibits them and prevents transcriptional activation of Hedgehog signaling pathway target genes. GLI transcription factor phosphorylation is inhibited by interaction of PRKACA with SMO which sequesters PRKACA at the cell membrane. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis most probably through the regulation of OFD1 in ciliogenesis. 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. Phosphorylates HSF1; this phosphorylation promotes HSF1 nuclear localization and transcriptional activity upon heat shock. Acts as a negative regulator of mTORC1 by mediating phosphorylation of RPTOR ; [Isoform 2]: Phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation.
• Tissue Specificity: Isoform 1 is ubiquitous. Isoform 2 is sperm-specific and is enriched in pachytene spermatocytes but is not detected in round spermatids.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  MAPK sig.ling pathway (hsa04010)
  Ras sig.ling pathway (hsa04014)
  Calcium sig.ling pathway (hsa04020)
  cAMP sig.ling pathway (hsa04024)
  Chemokine sig.ling pathway (hsa04062)
  Oocyte meiosis (hsa04114)
  Autophagy - animal (hsa04140)
  Longevity regulating pathway (hsa04211)
  Longevity regulating pathway - multiple species (hsa04213)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Wnt sig.ling pathway (hsa04310)
  Hedgehog sig.ling pathway (hsa04340)
  Apelin sig.ling pathway (hsa04371)
  Tight junction (hsa04530)
  Gap junction (hsa04540)
  Platelet activation (hsa04611)
  Circadian entrainment (hsa04713)
  Thermogenesis (hsa04714)
  Long-term potentiation (hsa04720)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Olfactory transduction (hsa04740)
  Taste transduction (hsa04742)
  Inflammatory mediator regulation of TRP channels (hsa04750)
  Insulin sig.ling pathway (hsa04910)
  Insulin secretion (hsa04911)
  GnRH sig.ling pathway (hsa04912)
  Ovarian steroidogenesis (hsa04913)
  Progesterone-mediated oocyte maturation (hsa04914)
  Estrogen sig.ling pathway (hsa04915)
  Melanogenesis (hsa04916)
  Thyroid hormone synthesis (hsa04918)
  Thyroid hormone sig.ling pathway (hsa04919)
  Oxytocin sig.ling pathway (hsa04921)
  Glucagon sig.ling pathway (hsa04922)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Aldosterone synthesis and secretion (hsa04925)
  Relaxin sig.ling pathway (hsa04926)
  Cortisol synthesis and secretion (hsa04927)
  Parathyroid hormone synthesis, secretion and action (hsa04928)
  Cushing syndrome (hsa04934)
  Growth hormone synthesis, secretion and action (hsa04935)
  Endocrine and other factor-regulated calcium reabsorption (hsa04961)
  Vasopressin-regulated water reabsorption (hsa04962)
  Salivary secretion (hsa04970)
  Gastric acid secretion (hsa04971)
  Bile secretion (hsa04976)
  Parkinson disease (hsa05012)
  Prion disease (hsa05020)
  Cocaine addiction (hsa05030)
  Amphetamine addiction (hsa05031)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Vibrio cholerae infection (hsa05110)
  Amoebiasis (hsa05146)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  PKA-mediated phosphorylation of key metabolic factors (R-HSA-163358)
  Triglyceride catabolism (R-HSA-163560)
  PKA activation (R-HSA-163615)
  PKA activation in glucagon signalling (R-HSA-164378)
  DARPP-32 events (R-HSA-180024)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  Rap1 signalling (R-HSA-392517)
  Regulation of insulin secretion (R-HSA-422356)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  CREB1 phosphorylation through the activation of Adenylate Cyclase (R-HSA-442720)
  Interleukin-3, Interleukin-5 and GM-CSF signaling (R-HSA-512988)
  Ion homeostasis (R-HSA-5578775)
  Degradation of GLI1 by the proteasome (R-HSA-5610780)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)
  GLI3 is processed to GLI3R by the proteasome (R-HSA-5610785)
  Hedgehog 'off' state (R-HSA-5610787)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  CD209 (DC-SIGN) signaling (R-HSA-5621575)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  RET signaling (R-HSA-8853659)
  AURKA Activation by TPX2 (R-HSA-8854518)
  HDL assembly (R-HSA-8963896)
  ROBO receptors bind AKAP5 (R-HSA-9010642)
  Loss of phosphorylation of MECP2 at T308 (R-HSA-9022535)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  GPER1 signaling (R-HSA-9634597)
  Regulation of glycolysis by fructose 2,6-bisphosphate metabolism (R-HSA-9634600)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  FCGR3A-mediated IL10 synthesis (R-HSA-9664323)
  Factors involved in megakaryocyte development and platelet production (R-HSA-983231)
  PKA-mediated phosphorylation of CREB (R-HSA-111931)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cardioacrofacial dysplasia 1	DIS39QWT	Strong	Autosomal dominant	[1]
Pigmented nodular adrenocortical disease, primary, 4	DISNQ3N7	Limited	Unknown	[2]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[11]

17 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[6]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[7]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[8]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[9]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[10]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[13]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[16]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[17]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[18]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[19]
Forskolin	DM6ITNG	Investigative	Forskolin increases the activity of cAMP-dependent protein kinase catalytic subunit alpha (PRKACA).	[20]

References

• [1] Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome. Am J Hum Genet. 2020 Nov 5;107(5):977-988. doi: 10.1016/j.ajhg.2020.09.005. Epub 2020 Oct 14.
• [2] Identification and characterization of novel mutations in the human gene encoding the catalytic subunit Calpha of protein kinase A (PKA). PLoS One. 2012;7(4):e34838. doi: 10.1371/journal.pone.0034838. Epub 2012 Apr 13.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [5] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [8] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] Caffeine programs hepatic SIRT1-related cholesterol synthesis and hypercholesterolemia via A2AR/cAMP/PKA pathway in adult male offspring rats. Toxicology. 2019 Apr 15;418:11-21.
• [15] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [16] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [17] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [18] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [19] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [20] Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK. Chem Biol Interact. 2017 Aug 1;273:107-114. doi: 10.1016/j.cbi.2017.06.005. Epub 2017 Jun 7.