Target Information
Target General Infomation | |||||
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Target ID |
T23995
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Former ID |
TTDC00178
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Target Name |
Protein kinase C, theta type
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Gene Name |
PRKCQ
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Synonyms |
NPKC-theta; Protein kinase C theta; nPKC-theta; Protein kinase C theta; PRKCQ
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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] | ||||
Renal transplantation [ICD9: 279.5; ICD10: D89.8] | |||||
Function |
Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non- redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non- canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1.
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BioChemical Class |
Kinase
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Target Validation |
T23995
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UniProt ID | |||||
EC Number |
EC 2.7.11.13
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Sequence |
MSPFLRIGLSNFDCGSCQSCQGEAVNPYCAVLVKEYVESENGQMYIQKKPTMYPPWDSTF
DAHINKGRVMQIIVKGKNVDLISETTVELYSLAERCRKNNGKTEIWLELKPQGRMLMNAR YFLEMSDTKDMNEFETEGFFALHQRRGAIKQAKVHHVKCHEFTATFFPQPTFCSVCHEFV WGLNKQGYQCRQCNAAIHKKCIDKVIAKCTGSAINSRETMFHKERFKIDMPHRFKVYNYK SPTFCEHCGTLLWGLARQGLKCDACGMNVHHRCQTKVANLCGINQKLMAEALAMIESTQQ ARCLRDTEQIFREGPVEIGLPCSIKNEARPPCLPTPGKREPQGISWESPLDEVDKMCHLP EPELNKERPSLQIKLKIEDFILHKMLGKGSFGKVFLAEFKKTNQFFAIKALKKDVVLMDD DVECTMVEKRVLSLAWEHPFLTHMFCTFQTKENLFFVMEYLNGGDLMYHIQSCHKFDLSR ATFYAAEIILGLQFLHSKGIVYRDLKLDNILLDKDGHIKIADFGMCKENMLGDAKTNTFC GTPDYIAPEILLGQKYNHSVDWWSFGVLLYEMLIGQSPFHGQDEEELFHSIRMDNPFYPR WLEKEAKDLLVKLFVREPEKRLGVRGDIRQHPLFREINWEELERKEIDPPFRPKVKSPFD CSNFDKEFLNEKPRLSFADRALINSMDQNMFRNFSFMNPGMERLIS |
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Structure |
1XJD; 2ENJ; 2ENN; 2ENZ; 2JED; 4Q9Z; 4RA5
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Drugs and Mode of Action | |||||
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-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] | |||
CDE-6960 | Drug Info | [548365] | |||
Indolocarbazole analogue | Drug Info | [526234] | |||
LY-317644 | Drug Info | [551283] | |||
LY-326449 | Drug Info | [534154] | |||
Phosphonoserine | Drug Info | [551393] | |||
Phosphonothreonine | Drug Info | [551393] | |||
RO-316233 | Drug Info | [528701] | |||
Ro-32-0557 | Drug Info | [551264] | |||
RO-320432 | Drug Info | [551264] | |||
Sotrastaurin acetate | Drug Info | [537117] | |||
[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] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | NF-kappa B signaling pathway | ||||
Vascular smooth muscle contraction | |||||
Tight junction | |||||
T cell receptor signaling pathway | |||||
Inflammatory mediator regulation of TRP channels | |||||
Adipocytokine signaling pathway | |||||
Measles | |||||
PANTHER 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 | |||||
Muscarinic acetylcholine receptor 1 and 3 signaling pathway | |||||
T cell activation | |||||
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 | ||||
TCR signaling in na& | |||||
#xef | |||||
ve CD4+ T cells | |||||
Calcineurin-regulated NFAT-dependent transcription in lymphocytes | |||||
TCR signaling in na& | |||||
ve CD8+ T cells | |||||
Thromboxane A2 receptor signaling | |||||
Role of Calcineurin-dependent NFAT signaling in lymphocytes | |||||
Downstream signaling in na& | |||||
Reactome | Apoptotic cleavage of cellular proteins | ||||
Effects of PIP2 hydrolysis | |||||
Inactivation, recovery and regulation of the phototransduction cascade | |||||
FCERI mediated NF-kB activation | |||||
G alpha (z) signalling events | |||||
WikiPathways | TCR Signaling Pathway | ||||
Calcium Regulation in the Cardiac Cell | |||||
Insulin Signaling | |||||
Wnt Signaling Pathway | |||||
Wnt Signaling Pathway and Pluripotency | |||||
G Protein Signaling Pathways | |||||
Myometrial Relaxation and Contraction Pathways | |||||
Fc epsilon receptor (FCERI) signaling | |||||
Corticotropin-releasing hormone | |||||
Signaling Pathways in Glioblastoma | |||||
miRs in Muscle Cell Differentiation | |||||
TCR signaling | |||||
Netrin-1 signaling | |||||
GPCR downstream signaling | |||||
Effects of PIP2 hydrolysis | |||||
Apoptotic execution phase | |||||
References | |||||
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 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 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 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) | ||||
Ref 551264 | Bisindolylmaleimide inhibitors of protein kinase C. Further conformational restriction of a tertiary amine side chain, Bioorg. Med. Chem. Lett. 4(11):1303-1308 (1994). |
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