Target Information
Target General Infomation | |||||
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Target ID |
T00895
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Former ID |
TTDC00066
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Target Name |
Protein kinase C, epsilon type
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Gene Name |
PRKCE
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Synonyms |
NPKC-epsilon; PKC epsilon; Protein Kinase C epsilon; PRKCE
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Target Type |
Clinical Trial
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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.
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BioChemical Class |
Kinase
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Target Validation |
T00895
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UniProt ID | |||||
EC Number |
EC 2.7.11.13
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Sequence |
MVVFNGLLKIKICEAVSLKPTAWSLRHAVGPRPQTFLLDPYIALNVDDSRIGQTATKQKT
NSPAWHDEFVTDVCNGRKIELAVFHDAPIGYDDFVANCTIQFEELLQNGSRHFEDWIDLE PEGRVYVIIDLSGSSGEAPKDNEERVFRERMRPRKRQGAVRRRVHQVNGHKFMATYLRQP TYCSHCRDFIWGVIGKQGYQCQVCTCVVHKRCHELIITKCAGLKKQETPDQVGSQRFSVN MPHKFGIHNYKVPTFCDHCGSLLWGLLRQGLQCKVCKMNVHRRCETNVAPNCGVDARGIA KVLADLGVTPDKITNSGQRRKKLIAGAESPQPASGSSPSEEDRSKSAPTSPCDQEIKELE NNIRKALSFDNRGEEHRAASSPDGQLMSPGENGEVRQGQAKRLGLDEFNFIKVLGKGSFG KVMLAELKGKDEVYAVKVLKKDVILQDDDVDCTMTEKRILALARKHPYLTQLYCCFQTKD RLFFVMEYVNGGDLMFQIQRSRKFDEPRSRFYAAEVTSALMFLHQHGVIYRDLKLDNILL DAEGHCKLADFGMCKEGILNGVTTTTFCGTPDYIAPEILQELEYGPSVDWWALGVLMYEM MAGQPPFEADNEDDLFESILHDDVLYPVWLSKEAVSILKAFMTKNPHKRLGCVASQNGED AIKQHPFFKEIDWVLLEQKKIKPPFKPRIKTKRDVNNFDQDFTREEPVLTLVDEAIVKQI NQEEFKGFSYFGEDLMP |
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Structure |
2WH0
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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& | |||||
#xef | |||||
ve CD4+ T cells | |||||
LPA4-mediated signaling events | |||||
CDC42 signaling events | |||||
TCR signaling in na& | |||||
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& | |||||
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 521504 | ClinicalTrials.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 545975 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005586) | ||||
Ref 546513 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008685) | ||||
Ref 525575 | Bioorg 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 526234 | Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues. | ||||
Ref 528032 | J Med Chem. 2006 Feb 23;49(4):1271-81.Design, synthesis, and biological evaluation of 3,4-diarylmaleimides as angiogenesis inhibitors. | ||||
Ref 528701 | J Med Chem. 1992 Jan;35(1):177-84.Inhibitors of protein kinase C. 1. 2,3-Bisarylmaleimides. | ||||
Ref 528755 | J 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 534154 | J 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 535231 | Protein kinase epsilon dampens the secretory response of model intestinal epithelia during ischemia. Surgery. 2001 Aug;130(2):310-8. | ||||
Ref 544337 | Protein kinase C, an elusive therapeutic target?. Nat Rev Drug Discov. 2012 December; 11(12): 937-957. | ||||
Ref 548365 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025002) |
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