General Information of Drug Off-Target (DOT) (ID: OT7J0P9L)

DOT Name Protein kinase C epsilon type (PRKCE)
Synonyms EC 2.7.11.13; nPKC-epsilon
Gene Name PRKCE
UniProt ID
KPCE_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
2WH0; 5LIH
EC Number
2.7.11.13
Pfam ID
PF00130 ; PF00168 ; PF00069 ; PF00433
Sequence
MVVFNGLLKIKICEAVSLKPTAWSLRHAVGPRPQTFLLDPYIALNVDDSRIGQTATKQKT
NSPAWHDEFVTDVCNGRKIELAVFHDAPIGYDDFVANCTIQFEELLQNGSRHFEDWIDLE
PEGRVYVIIDLSGSSGEAPKDNEERVFRERMRPRKRQGAVRRRVHQVNGHKFMATYLRQP
TYCSHCRDFIWGVIGKQGYQCQVCTCVVHKRCHELIITKCAGLKKQETPDQVGSQRFSVN
MPHKFGIHNYKVPTFCDHCGSLLWGLLRQGLQCKVCKMNVHRRCETNVAPNCGVDARGIA
KVLADLGVTPDKITNSGQRRKKLIAGAESPQPASGSSPSEEDRSKSAPTSPCDQEIKELE
NNIRKALSFDNRGEEHRAASSPDGQLMSPGENGEVRQGQAKRLGLDEFNFIKVLGKGSFG
KVMLAELKGKDEVYAVKVLKKDVILQDDDVDCTMTEKRILALARKHPYLTQLYCCFQTKD
RLFFVMEYVNGGDLMFQIQRSRKFDEPRSRFYAAEVTSALMFLHQHGVIYRDLKLDNILL
DAEGHCKLADFGMCKEGILNGVTTTTFCGTPDYIAPEILQELEYGPSVDWWALGVLMYEM
MAGQPPFEADNEDDLFESILHDDVLYPVWLSKEAVSILKAFMTKNPHKRLGCVASQNGED
AIKQHPFFKEIDWVLLEQKKIKPPFKPRIKTKRDVNNFDQDFTREEPVLTLVDEAIVKQI
NQEEFKGFSYFGEDLMP
Function
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays essential roles in the regulation of multiple cellular processes linked to cytoskeletal proteins, such as cell adhesion, motility, migration and cell cycle, functions in neuron growth and ion channel regulation, and is involved in immune response, cancer cell invasion and regulation of apoptosis. Mediates cell adhesion to the extracellular matrix via integrin-dependent signaling, by mediating angiotensin-2-induced activation of integrin beta-1 (ITGB1) in cardiac fibroblasts. Phosphorylates MARCKS, which phosphorylates and activates PTK2/FAK, leading to the spread of cardiomyocytes. Involved in the control of the directional transport of ITGB1 in mesenchymal cells by phosphorylating vimentin (VIM), an intermediate filament (IF) protein. In epithelial cells, associates with and phosphorylates keratin-8 (KRT8), which induces targeting of desmoplakin at desmosomes and regulates cell-cell contact. Phosphorylates IQGAP1, which binds to CDC42, mediating epithelial cell-cell detachment prior to migration. In HeLa cells, contributes to hepatocyte growth factor (HGF)-induced cell migration, and in human corneal epithelial cells, plays a critical role in wound healing after activation by HGF. During cytokinesis, forms a complex with YWHAB, which is crucial for daughter cell separation, and facilitates abscission by a mechanism which may implicate the regulation of RHOA. In cardiac myocytes, regulates myofilament function and excitation coupling at the Z-lines, where it is indirectly associated with F-actin via interaction with COPB1. During endothelin-induced cardiomyocyte hypertrophy, mediates activation of PTK2/FAK, which is critical for cardiomyocyte survival and regulation of sarcomere length. Plays a role in the pathogenesis of dilated cardiomyopathy via persistent phosphorylation of troponin I (TNNI3). Involved in nerve growth factor (NFG)-induced neurite outgrowth and neuron morphological change independently of its kinase activity, by inhibition of RHOA pathway, activation of CDC42 and cytoskeletal rearrangement. May be involved in presynaptic facilitation by mediating phorbol ester-induced synaptic potentiation. Phosphorylates gamma-aminobutyric acid receptor subunit gamma-2 (GABRG2), which reduces the response of GABA receptors to ethanol and benzodiazepines and may mediate acute tolerance to the intoxicating effects of ethanol. Upon PMA treatment, phosphorylates the capsaicin- and heat-activated cation channel TRPV1, which is required for bradykinin-induced sensitization of the heat response in nociceptive neurons. Is able to form a complex with PDLIM5 and N-type calcium channel, and may enhance channel activities and potentiates fast synaptic transmission by phosphorylating the pore-forming alpha subunit CACNA1B (CaV2.2). In prostate cancer cells, interacts with and phosphorylates STAT3, which increases DNA-binding and transcriptional activity of STAT3 and seems to be essential for prostate cancer cell invasion. Downstream of TLR4, plays an important role in the lipopolysaccharide (LPS)-induced immune response by phosphorylating and activating TICAM2/TRAM, which in turn activates the transcription factor IRF3 and subsequent cytokines production. In differentiating erythroid progenitors, is regulated by EPO and controls the protection against the TNFSF10/TRAIL-mediated apoptosis, via BCL2. May be involved in the regulation of the insulin-induced phosphorylation and activation of AKT1. Phosphorylates NLRP5/MATER and may thereby modulate AKT pathway activation in cumulus cells.
Tissue Specificity Expressed in cumulus cells (at protein level).
KEGG Pathway
cGMP-PKG sig.ling pathway (hsa04022 )
Sphingolipid sig.ling pathway (hsa04071 )
Vascular smooth muscle contraction (hsa04270 )
Apelin sig.ling pathway (hsa04371 )
Tight junction (hsa04530 )
Fc gamma R-mediated phagocytosis (hsa04666 )
Inflammatory mediator regulation of TRP channels (hsa04750 )
Aldosterone synthesis and secretion (hsa04925 )
Type II diabetes mellitus (hsa04930 )
Insulin resistance (hsa04931 )
AGE-RAGE sig.ling pathway in diabetic complications (hsa04933 )
Shigellosis (hsa05131 )
MicroR.s in cancer (hsa05206 )
Reactome Pathway
SHC1 events in ERBB2 signaling (R-HSA-1250196 )
DAG and IP3 signaling (R-HSA-1489509 )
Role of phospholipids in phagocytosis (R-HSA-2029485 )
G alpha (z) signalling events (R-HSA-418597 )
Effects of PIP2 hydrolysis (R-HSA-114508 )

Molecular Interaction Atlas (MIA) of This DOT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
19 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Protein kinase C epsilon type (PRKCE). [1]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Protein kinase C epsilon type (PRKCE). [2]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Protein kinase C epsilon type (PRKCE). [3]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Protein kinase C epsilon type (PRKCE). [4]
Troglitazone DM3VFPD Approved Troglitazone decreases the expression of Protein kinase C epsilon type (PRKCE). [6]
Indomethacin DMSC4A7 Approved Indomethacin increases the expression of Protein kinase C epsilon type (PRKCE). [7]
Obeticholic acid DM3Q1SM Approved Obeticholic acid increases the expression of Protein kinase C epsilon type (PRKCE). [8]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of Protein kinase C epsilon type (PRKCE). [10]
Curcumin DMQPH29 Phase 3 Curcumin decreases the expression of Protein kinase C epsilon type (PRKCE). [11]
phorbol 12-myristate 13-acetate DMJWD62 Phase 2 phorbol 12-myristate 13-acetate decreases the expression of Protein kinase C epsilon type (PRKCE). [12]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Protein kinase C epsilon type (PRKCE). [14]
Trichostatin A DM9C8NX Investigative Trichostatin A increases the expression of Protein kinase C epsilon type (PRKCE). [17]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of Protein kinase C epsilon type (PRKCE). [18]
methyl p-hydroxybenzoate DMO58UW Investigative methyl p-hydroxybenzoate decreases the expression of Protein kinase C epsilon type (PRKCE). [19]
NSC-1771 DMNXDGQ Investigative NSC-1771 decreases the activity of Protein kinase C epsilon type (PRKCE). [21]
Morin DM2OGZ5 Investigative Morin decreases the expression of Protein kinase C epsilon type (PRKCE). [22]
LICOAGROCHACONE A DMWY0TN Investigative LICOAGROCHACONE A decreases the expression of Protein kinase C epsilon type (PRKCE). [23]
OXYRESVERATROL DMN7S4L Investigative OXYRESVERATROL increases the expression of Protein kinase C epsilon type (PRKCE). [24]
Bisindolylmaleimide-I DMOQJZC Investigative Bisindolylmaleimide-I decreases the expression of Protein kinase C epsilon type (PRKCE). [24]
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⏷ Show the Full List of 19 Drug(s)
4 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of Protein kinase C epsilon type (PRKCE). [5]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Protein kinase C epsilon type (PRKCE). [13]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the methylation of Protein kinase C epsilon type (PRKCE). [16]
Hexadecanoic acid DMWUXDZ Investigative Hexadecanoic acid increases the phosphorylation of Protein kinase C epsilon type (PRKCE). [20]
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2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
Deoxycholic acid DM3GYAL Approved Deoxycholic acid increases the cleavage of Protein kinase C epsilon type (PRKCE). [9]
Droloxifene DM9JPUD Discontinued in Phase 2 Droloxifene affects the localization of Protein kinase C epsilon type (PRKCE). [15]
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References

1 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.
2 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
3 Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
4 Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
5 Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
6 Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
7 Overexpression of protein kinase C-beta1 isoenzyme suppresses indomethacin-induced apoptosis in gastric epithelial cells. Gastroenterology. 2000 Mar;118(3):507-14. doi: 10.1016/s0016-5085(00)70256-3.
8 Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
9 Prevention of deoxycholate-induced gastric apoptosis by aspirin: roles of NF-kappaB and PKC signaling. J Surg Res. 2008 Mar;145(1):66-73. doi: 10.1016/j.jss.2007.04.039. Epub 2007 Jul 20.
10 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
11 Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
12 Protein kinase C inhibitors alter neurotensin receptor binding and function in prostate cancer PC3 cells. Regul Pept. 2008 Apr 10;147(1-3):96-109. doi: 10.1016/j.regpep.2008.01.009. Epub 2008 Feb 11.
13 Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
14 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.
15 Tamoxifen induces selective membrane association of protein kinase C epsilon in MCF-7 human breast cancer cells. Int J Cancer. 1998 Sep 11;77(6):928-32. doi: 10.1002/(sici)1097-0215(19980911)77:6<928::aid-ijc22>3.0.co;2-w.
16 DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
17 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
18 In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
19 Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
20 Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.
21 PKC sulfhydryl targeting by disulfiram produces divergent isozymic regulatory responses that accord with the cancer preventive activity of the thiuram disulfide. Antioxid Redox Signal. 2005 Jul-Aug;7(7-8):855-62. doi: 10.1089/ars.2005.7.855.
22 Molecular mechanism of anti-cancerous potential of Morin extracted from mulberry in Hela cells. Food Chem Toxicol. 2018 Feb;112:466-475. doi: 10.1016/j.fct.2017.07.002. Epub 2017 Jul 6.
23 Licochalcone A from licorice root, an inhibitor of human hepatoma cell growth via induction of cell apoptosis and cell cycle arrest. Food Chem Toxicol. 2018 Oct;120:407-417. doi: 10.1016/j.fct.2018.07.044. Epub 2018 Jul 25.
24 Oxyresveratrol improves tight junction integrity through the PKC and MAPK signaling pathways in Caco-2?cells. Food Chem Toxicol. 2017 Oct;108(Pt A):203-213. doi: 10.1016/j.fct.2017.08.002. Epub 2017 Aug 2.