Target General Infomation
Target ID
T00895
Former ID
TTDC00066
Target Name
Protein kinase C, epsilon type
Gene Name
PRKCE
Synonyms
NPKC-epsilon; PKC epsilon; Protein Kinase C epsilon; PRKCE
Target Type
Clinical Trial
Disease Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Ischemic reperfusion injury [ICD10: I00-I99]
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 toethanol 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 isrequired 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 byphosphorylating 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.
BioChemical Class
Kinase
Target Validation
T00895
UniProt ID
EC Number
EC 2.7.11.13
Sequence
MVVFNGLLKIKICEAVSLKPTAWSLRHAVGPRPQTFLLDPYIALNVDDSRIGQTATKQKT
NSPAWHDEFVTDVCNGRKIELAVFHDAPIGYDDFVANCTIQFEELLQNGSRHFEDWIDLE
PEGRVYVIIDLSGSSGEAPKDNEERVFRERMRPRKRQGAVRRRVHQVNGHKFMATYLRQP
TYCSHCRDFIWGVIGKQGYQCQVCTCVVHKRCHELIITKCAGLKKQETPDQVGSQRFSVN
MPHKFGIHNYKVPTFCDHCGSLLWGLLRQGLQCKVCKMNVHRRCETNVAPNCGVDARGIA
KVLADLGVTPDKITNSGQRRKKLIAGAESPQPASGSSPSEEDRSKSAPTSPCDQEIKELE
NNIRKALSFDNRGEEHRAASSPDGQLMSPGENGEVRQGQAKRLGLDEFNFIKVLGKGSFG
KVMLAELKGKDEVYAVKVLKKDVILQDDDVDCTMTEKRILALARKHPYLTQLYCCFQTKD
RLFFVMEYVNGGDLMFQIQRSRKFDEPRSRFYAAEVTSALMFLHQHGVIYRDLKLDNILL
DAEGHCKLADFGMCKEGILNGVTTTTFCGTPDYIAPEILQELEYGPSVDWWALGVLMYEM
MAGQPPFEADNEDDLFESILHDDVLYPVWLSKEAVSILKAFMTKNPHKRLGCVASQNGED
AIKQHPFFKEIDWVLLEQKKIKPPFKPRIKTKRDVNNFDQDFTREEPVLTLVDEAIVKQI
NQEEFKGFSYFGEDLMP
Structure
2WH0
Drugs and Mode of Action
Drug(s) Bryostatin-1 Drug Info Phase 2 Discovery agent [521504]
KAI-1455 Drug Info Discontinued in Phase 1 Ischemic reperfusion injury [548522]
CDE-6960 Drug Info Terminated Inflammatory disease [548364]
LY-317644 Drug Info Terminated Discovery agent [546513]
RO-320432 Drug Info Terminated Discovery agent [541291], [545975]
Activator 13-acetate Drug Info [535231]
Bryostatin-1 Drug Info [535231]
Phorbol 12-myristate Drug Info [535231]
Inhibitor 2,3,3-Triphenyl-acrylonitrile Drug Info [528755]
2-(4-Hydroxy-phenyl)-3,3-diphenyl-acrylonitrile Drug Info [528755]
3,3-Bis-(4-hydroxy-phenyl)-2-phenyl-acrylonitrile Drug Info [528755]
3,3-Bis-(4-methoxy-phenyl)-2-phenyl-acrylonitrile Drug Info [528755]
3,4-di-(4-methoxyphenyl)-1H-pyrrole-2,5-dione Drug Info [528032]
3,4-diphenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(4-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile Drug Info [528755]
3-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
3-(indole-3-yl)-4-phenyl-1H-pyrrole-2,5-dione Drug Info [528032]
4-cycloheptyliden(4-hydroxyphenyl)methylphenol Drug Info [528755]
4-cyclohexyliden(4-hydroxyphenyl)methylphenol Drug Info [528755]
4-[1-(4-hydroxyphenyl)-3-methyl-1-butenyl]phenol Drug Info [528755]
CDE-6960 Drug Info [548365]
Indolocarbazole analogue Drug Info [526234]
LY-317644 Drug Info [551283]
LY-326449 Drug Info [534154]
RO-316233 Drug Info [528701]
Ro-32-0557 Drug Info [551264]
RO-320432 Drug Info [551264]
[2,2':5',2'']Terthiophen-4-yl-methanol Drug Info [525575]
[2,2':5',2'']Terthiophene-4,5''-dicarbaldehyde Drug Info [525575]
[2,2':5',2'']Terthiophene-4-carbaldehyde Drug Info [525575]
Stimulator KAI-1455 Drug Info [544337]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway cGMP-PKG signaling pathway
Sphingolipid signaling pathway
Vascular smooth muscle contraction
Tight junction
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
Inflammatory mediator regulation of TRP channels
Type II diabetes mellitus
MicroRNAs in cancer
NetPath Pathway IL2 Signaling Pathway
PANTHER Pathway Alpha adrenergic receptor signaling pathway
Alzheimer disease-amyloid secretase pathway
Angiogenesis
Apoptosis signaling pathway
EGF receptor signaling pathway
Endothelin signaling pathway
FGF signaling pathway
Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway
Inflammation mediated by chemokine and cytokine signaling pathway
Muscarinic acetylcholine receptor 1 and 3 signaling pathway
VEGF signaling pathway
Wnt signaling pathway
5HT2 type receptor mediated signaling pathway
Histamine H1 receptor mediated signaling pathway
Oxytocin receptor mediated signaling pathway
Thyrotropin-releasing hormone receptor signaling pathway
CCKR signaling map ST
Pathway Interaction Database Endothelins
LPA receptor mediated events
TCR signaling in na&amp
#xef
ve CD4+ T cells
LPA4-mediated signaling events
CDC42 signaling events
TCR signaling in na&amp
ve CD8+ T cells
Thromboxane A2 receptor signaling
Role of Calcineurin-dependent NFAT signaling in lymphocytes
IL2-mediated signaling events
PDGFR-beta signaling pathway
IL8- and CXCR1-mediated signaling events
Regulation of Ras family activation
Downstream signaling in na&amp
Reactome Effects of PIP2 hydrolysis
DAG and IP3 signaling
Role of phospholipids in phagocytosis
G alpha (z) signalling events
WikiPathways Hypothetical Network for Drug Addiction
Calcium Regulation in the Cardiac Cell
Wnt Signaling Pathway
Wnt Signaling Pathway and Pluripotency
G Protein Signaling Pathways
Myometrial Relaxation and Contraction Pathways
Oncostatin M Signaling Pathway
miRs in Muscle Cell Differentiation
GPCR downstream signaling
Effects of PIP2 hydrolysis
Physiological and Pathological Hypertrophy of the Heart
References
Ref 521504ClinicalTrials.gov (NCT00031694) Paclitaxel and Bryostatin 1 in Treating Patients With Advanced Pancreatic Cancer. U.S. National Institutes of Health.
Ref 541291(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: 6034).
Ref 545975Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005586)
Ref 546513Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008685)
Ref 548364Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025002)
Ref 548522Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800026294)
Ref 525575Bioorg Med Chem Lett. 1999 Aug 2;9(15):2279-82.Novel protein kinase C inhibitors: synthesis and PKC inhibition of beta-substituted polythiophene derivatives.
Ref 526234Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues.
Ref 528032J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors.
Ref 528701J Med Chem. 1992 Jan;35(1):177-84.Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides.
Ref 528755J Med Chem. 1992 Feb 7;35(3):573-83.Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation.
Ref 534154J Med Chem. 1996 Jul 5;39(14):2664-71.(S)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16, 21-dimetheno-1H, 13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-d ione (LY333531) and related analogues: isozyme selective inhibitors of protein kinase C beta.
Ref 535231Protein kinase epsilon dampens the secretory response of model intestinal epithelia during ischemia. Surgery. 2001 Aug;130(2):310-8.
Ref 544337Protein kinase C, an elusive therapeutic target?. Nat Rev Drug Discov. 2012 December; 11(12): 937-957.
Ref 548365Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025002)
Ref 551264Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994).
Ref 551283Synthesis of bisindolylmaleimide macrocycles, Bioorg. Med. Chem. Lett. 5(18):2093-2096 (1995).

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