Target General Infomation
Target ID
T44861
Former ID
TTDNC00553
Target Name
Protein kinase C, delta type
Gene Name
PRKCD
Synonyms
Protein kinase C delta type catalytic subunit; SDK1; Tyrosine-protein kinase PRKCD; nPKC-delta; NPKC-delta; Protein Kinase C delta; PKC-delta; PRKCD
Target Type
Clinical Trial
Disease Human immunodeficiency virus infection [ICD9: 279.3; ICD10: B20-B26]
Reperfusion injury and heart attacks; Acute myocardial infarction [ICD9: 410; ICD10: I21, I21-I22, I22]
Function
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that plays contrasting roles in cell death and cell survival by functioning as a pro-apoptotic protein during DNA damage-induced apoptosis, but acting as an anti-apoptotic protein during cytokine receptor- initiated cell death, is involved in tumor suppression as wellas survival of several cancers, is required for oxygen radical production by NADPH oxidase and acts as positive or negative regulator in platelet functional responses. Negatively regulates B cell proliferation and also has an important function in self- antigen induced B cell tolerance induction. Upon DNA damage, activates the promoter of the death-promoting transcription factor BCLAF1/Btf to trigger BCLAF1-mediated p53/TP53 gene transcription and apoptosis. In response to oxidative stress, interact with and activate CHUK/IKKA in the nucleus, causing the phosphorylation of p53/TP53. In the case of ER stress or DNA damage-induced apoptosis, can form a complex with the tyrosine-protein kinase ABL1 which trigger apoptosis independently of p53/TP53. In cytosol can trigger apoptosis by activating MAPK11 or MAPK14, inhibiting AKT1 and decreasing the level of X-linked inhibitor of apoptosis protein (XIAP), whereas in nucleus induces apoptosis via the activation of MAPK8 or MAPK9. Upon ionizing radiation treatment, is required for the activation of the apoptosis regulators BAX and BAK, which trigger the mitochondrial cell death pathway. Can phosphorylate MCL1 and target it for degradationwhich is sufficient to trigger for BAX activation and apoptosis. Is required for the control of cell cycle progression both at G1/S and G2/M phases. Mediates phorbol 12-myristate 13-acetate (PMA)- induced inhibition of cell cycle progression at G1/S phase by up- regulating the CDK inhibitor CDKN1A/p21 and inhibiting the cyclin CCNA2 promoter activity. In response to UV irradiation can phosphorylate CDK1, which is important for the G2/M DNA damage checkpoint activation. Can protect glioma cells from the apoptosis induced by TNFSF10/TRAIL, probably by inducing increased phosphorylation and subsequent activation of AKT1. Is highly expressed in a number of cancer cells and promotes cell survival and resistance against chemotherapeutic drugs by inducing cyclin D1 (CCND1) and hyperphosphorylation of RB1, and via several pro- survival pathways, including NF-kappa-B, AKT1 and MAPK1/3 (ERK1/2). Can also act as tumor suppressor upon mitogenic stimulation with PMA or TPA. In N-formyl-methionyl-leucyl- phenylalanine (fMLP)-treated cells, is required for NCF1 (p47- phox) phosphorylation and activation of NADPH oxidase activity, and regulates TNF-elicited superoxide anion production in neutrophils, by direct phosphorylation and activation of NCF1 or indirectly through MAPK1/3 (ERK1/2) signaling pathways. May also play a role in the regulation of NADPH oxidase activity in eosinophil after stimulation with IL5, leukotriene B4 or PMA. In collagen-induced platelet aggregation, acts a negative regulator of filopodia formation and actin polymerization by interacting with and negatively regulating VASP phosphorylation. Downstream of PAR1, PAR4 and CD36/GP4 receptors, regulates differentially platelet dense granule secretion; acts as a positive regulator in PAR-mediated granule secretion, whereas it negatively regulates CD36/GP4-mediated granule release. Phosphorylates MUC1 in the C- terminal and regulates the interaction between MUC1 and beta- catenin. The catalytic subunit phosphorylates 14-3-3 proteins (YWHAB, YWHAZ and YWHAH) in a sphingosine-dependent fashion (By similarity).
BioChemical Class
Kinase
Target Validation
T50951
UniProt ID
EC Number
EC 2.7.10.2
Sequence
MAPFLRIAFNSYELGSLQAEDEANQPFCAVKMKEALSTERGKTLVQKKPTMYPEWKSTFD
AHIYEGRVIQIVLMRAAEEPVSEVTVGVSVLAERCKKNNGKAEFWLDLQPQAKVLMSVQY
FLEDVDCKQSMRSEDEAKFPTMNRRGAIKQAKIHYIKNHEFIATFFGQPTFCSVCKDFVW
GLNKQGYKCRQCNAAIHKKCIDKIIGRCTGTAANSRDTIFQKERFNIDMPHRFKVHNYMS
PTFCDHCGSLLWGLVKQGLKCEDCGMNVHHKCREKVANLCGINQKLLAEALNQVTQRASR
RSDSASSEPVGIYQGFEKKTGVAGEDMQDNSGTYGKIWEGSSKCNINNFIFHKVLGKGSF
GKVLLGELKGRGEYFAIKALKKDVVLIDDDVECTMVEKRVLTLAAENPFLTHLICTFQTK
DHLFFVMEFLNGGDLMYHIQDKGRFELYRATFYAAEIMCGLQFLHSKGIIYRDLKLDNVL
LDRDGHIKIADFGMCKENIFGESRASTFCGTPDYIAPEILQGLKYTFSVDWWSFGVLLYE
MLIGQSPFHGDDEDELFESIRVDTPHYPRWITKESKDILEKLFEREPTKRLGVTGNIKIH
PFFKTINWTLLEKRRLEPPFRPKVKSPRDYSNFDQEFLNEKARLSYSDKNLIDSMDQSAF
AGFSFVNPKFEHLLED
Structure
1YRK; 2YUU
Drugs and Mode of Action
Drug(s) KAI-9803 Drug Info Phase 1/2 Reperfusion injury and heart attacks; Acute myocardial infarction [536497], [542782]
AD 198 Drug Info Terminated Discovery agent [544733]
LY-317644 Drug Info Terminated Discovery agent [546513]
RO-320432 Drug Info Terminated Discovery agent [541291], [545975]
Inhibitor 13-Acetylphorbol Drug Info [551374]
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-Hydroxy-phenyl)-2,3-diphenyl-acrylonitrile Drug Info [528755]
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]
INDOLACTUM Drug Info [526267]
Indolocarbazole analogue Drug Info [526234]
Ingenol-3-bezoate Drug Info [526058]
KAI-9803 Drug Info [536615], [536788], [537459]
LY-317644 Drug Info [551283]
LY-326449 Drug Info [534154]
Phorbol 12,13-butyrate Drug Info [528924]
PROSTRATIN Drug Info [527606]
RO-316233 Drug Info [528701]
Ro-32-0557 Drug Info [551264]
RO-320432 Drug Info [551264]
THYMELEATOXIN Drug Info [526058]
[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]
Activator AD 198 Drug Info [535627]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Chemokine signaling pathway
Vascular smooth muscle contraction
Tight junction
Fc epsilon RI signaling pathway
Fc gamma R-mediated phagocytosis
Neurotrophin signaling pathway
Inflammatory mediator regulation of TRP channels
GnRH signaling pathway
Estrogen signaling pathway
Type II diabetes mellitus
NetPath Pathway IL2 Signaling Pathway
PANTHER Pathway Alpha adrenergic receptor signaling pathway
Alzheimer disease-amyloid secretase pathway
Angiogenesis
Apoptosis signaling pathway
B cell activation
EGF receptor signaling pathway
Endothelin signaling pathway
FGF signaling pathway
Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated 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
Thromboxane A2 receptor signaling
Role of Calcineurin-dependent NFAT signaling in lymphocytes
IGF1 pathway
Ceramide signaling pathway
IFN-gamma pathway
ErbB1 downstream signaling
Syndecan-4-mediated signaling events
IL6-mediated signaling events
PDGFR-beta signaling pathway
Hedgehog signaling events mediated by Gli proteins
Signaling events mediated by VEGFR1 and VEGFR2
PAR1-mediated thrombin signaling events
Syndecan-2-mediated signaling events
Validated transcriptional targets of TAp63 isoforms
p53 pathway
Trk receptor signaling mediated by the MAPK pathway
Trk receptor signaling mediated by PI3K and PLC-gamma
Alpha-synuclein signaling
Reactome Apoptotic cleavage of cellular proteins
Calmodulin induced events
Effects of PIP2 hydrolysis
DAG and IP3 signaling
Role of phospholipids in phagocytosis
G alpha (z) signalling events
HuR (ELAVL1) binds and stabilizes mRNA
VEGFR2 mediated cell proliferation
CLEC7A (Dectin-1) signaling
Interferon gamma signaling
WikiPathways TCR Signaling Pathway
Type II interferon signaling (IFNG)
Calcium Regulation in the Cardiac Cell
Insulin Signaling
EGF/EGFR Signaling Pathway
Wnt Signaling Pathway
Wnt Signaling Pathway and Pluripotency
MAPK Signaling Pathway
IL-6 signaling pathway
G Protein Signaling Pathways
Myometrial Relaxation and Contraction Pathways
Regulation of mRNA Stability by Proteins that Bind AU-rich Elements
DAG and IP3 signaling
Alpha 6 Beta 4 signaling pathway
BDNF signaling pathway
Oncostatin M Signaling Pathway
Corticotropin-releasing hormone
AGE/RAGE pathway
B Cell Receptor Signaling Pathway
Signaling Pathways in Glioblastoma
miRs in Muscle Cell Differentiation
Opioid Signalling
GPCR downstream signaling
Effects of PIP2 hydrolysis
Apoptotic execution phase
Type II diabetes mellitus
References
Ref 536497Pharmacologic therapeutics for cardiac reperfusion injury. Expert Opin Emerg Drugs. 2007 Sep;12(3):367-88.
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 542782(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: 7840).
Ref 544733Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000772)
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 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 526058J Med Chem. 2001 May 24;44(11):1690-701.Structural basis of binding of high-affinity ligands to protein kinase C: prediction of the binding modes through a new molecular dynamics method and evaluation by site-directed mutagenesis.
Ref 526234Bioorg Med Chem Lett. 2002 Jan 21;12(2):147-50.Mixed lineage kinase activity of indolocarbazole analogues.
Ref 526267J Med Chem. 2002 Feb 14;45(4):853-60.Structural basis of RasGRP binding to high-affinity PKC ligands.
Ref 527606J Med Chem. 1992 May 29;35(11):1978-86.A nonpromoting phorbol from the samoan medicinal plant Homalanthus nutans inhibits cell killing by HIV-1.
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 528924J Med Chem. 2007 Jul 26;50(15):3465-81. Epub 2007 Jun 26.Conformationally constrained analogues of diacylglycerol (DAG). 28. DAG-dioxolanones reveal a new additional interaction site in the C1b domain of PKC delta.
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 535627Novel extranuclear-targeted anthracyclines override the antiapoptotic functions of Bcl-2 and target protein kinase C pathways to induce apoptosis. Mol Cancer Ther. 2002 May;1(7):469-81.
Ref 536615Intracoronary KAI-9803 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction. Circulation. 2008 Feb 19;117(7):886-96. Epub 2008 Feb 4.
Ref 536788Letter by Metzler et al regarding article, "Intracoronary KAI-9803 as an adjunct to primary coronary intervention for acute ST-segment elevation myocardial infarction". Circulation. 2008 Jul 22;118(4):e80.
Ref 537459PKC delta and epsilon in drug targeting and therapeutics. Recent Pat DNA Gene Seq. 2009;3(2):96-101.
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).
Ref 551374The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42.
Ref 1587926URL: https://www.ebi.ac.uk/chembl/ The ChEMBL database in 2017

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