Target Information
Target General Infomation | |||||
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Target ID |
T59190
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Former ID |
TTDR00557
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Target Name |
Protein kinase C, zeta type
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Gene Name |
PRKCZ
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Synonyms |
NPKC-zeta; Protein kinase C zeta; PRKCZ
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Target Type |
Discontinued
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Function |
Calcium- anddiacylglycerol-independent serine/threonine-protein kinase that functions in phosphatidylinositol 3-kinase (PI3K) pathway and mitogen-activated protein (MAP) kinase cascade, and is involved in NF-kappa-B activation, mitogenic signaling, cell proliferation, cell polarity, inflammatory response and maintenance of long-term potentiation (LTP). Upon lipopolysaccharide (LPS) treatment in macrophages, or following mitogenic stimuli, functions downstream of PI3K to activate MAP2K1/MEK1-MAPK1/ERK2 signaling cascade independently of RAF1 activation. Required for insulin-dependent activation of AKT3, but may function as an adapter rather than a direct activator. Upon insulin treatment may act as a downstream effector of PI3K and contribute to the activation of translocation of the glucose transporter SLC2A4/GLUT4 and subsequent glucose transport in adipocytes. In EGF-induced cells, binds and activates MAP2K5/MEK5-MAPK7/ERK5 independently of its kinase activity and can activate JUN promoter through MEF2C. Through binding with SQSTM1/p62, functions in interleukin-1 signaling and activation of NF-kappa-B with the specific adapters RIPK1 and TRAF6. Participates in TNF-dependent transactivation of NF-kappa-B by phosphorylating and activating IKBKB kinase, which in turn leads to the degradation of NF-kappa-B inhibitors. In migrating astrocytes, forms a cytoplasmic complex with PARD6A and is recruited by CDC42 to function in the establishment of cell polarity along with the microtubule motor and dynein. In association with FEZ1, stimulates neuronal differentiation in PC12 cells. In the inflammatory response, is required for the T-helper 2 (Th2) differentiation process, including interleukin production, efficient activation of JAK1 and the subsequent phosphorylation and nuclear translocation of STAT6. May be involved in development of allergic airway inflammation (asthma), a process dependent on Th2 immune response. In the NF-kappa-B-mediated inflammatory response, can relieve SETD6-dependent repression of NF-kappa-B target genes by phosphorylating the RELA subunit at 'Ser-311'. Necessary and sufficient for LTP maintenance in hippocampal CA1 pyramidal cells. In vein endothelial cells treated with the oxidant peroxynitrite, phosphorylates STK11 leading to nuclear export of STK11, subsequent inhibition of PI3K/Akt signaling, and increased apoptosis.
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BioChemical Class |
Kinase
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Target Validation |
T59190
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UniProt ID | |||||
EC Number |
EC 2.7.11.13
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Sequence |
MPSRTGPKMEGSGGRVRLKAHYGGDIFITSVDAATTFEELCEEVRDMCRLHQQHPLTLKW
VDSEGDPCTVSSQMELEEAFRLARQCRDEGLIIHVFPSTPEQPGLPCPGEDKSIYRRGAR RWRKLYRANGHLFQAKRFNRRAYCGQCSERIWGLARQGYRCINCKLLVHKRCHGLVPLTC RKHMDSVMPSQEPPVDDKNEDADLPSEETDGIAYISSSRKHDSIKDDSEDLKPVIDGMDG IKISQGLGLQDFDLIRVIGRGSYAKVLLVRLKKNDQIYAMKVVKKELVHDDEDIDWVQTE KHVFEQASSNPFLVGLHSCFQTTSRLFLVIEYVNGGDLMFHMQRQRKLPEEHARFYAAEI CIALNFLHERGIIYRDLKLDNVLLDADGHIKLTDYGMCKEGLGPGDTTSTFCGTPNYIAP EILRGEEYGFSVDWWALGVLMFEMMAGRSPFDIITDNPDMNTEDYLFQVILEKPIRIPRF LSVKASHVLKGFLNKDPKERLGCRPQTGFSDIKSHAFFRSIDWDLLEKKQALPPFQPQIT DDYGLDNFDTQFTSEPVQLTPDDEDAIKRIDQSEFEGFEYINPLLLSTEESV |
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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] | |||
Bisindolylmaleimide-I | Drug Info | [535047] | |||
Go6976 | Drug Info | [535047] | |||
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] | |||
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM) | |||||
TEP | EXP Info | ||||
Pathways | |||||
KEGG Pathway | Rap1 signaling pathway | ||||
Chemokine signaling pathway | |||||
Sphingolipid signaling pathway | |||||
Endocytosis | |||||
PI3K-Akt signaling pathway | |||||
Hippo signaling pathway | |||||
Tight junction | |||||
Platelet activation | |||||
Insulin signaling pathway | |||||
Type II diabetes mellitus | |||||
PANTHER Pathway | Alzheimer disease-amyloid secretase pathway | ||||
Angiogenesis | |||||
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 | |||||
Pathway Interaction Database | RhoA signaling pathway | ||||
Insulin Pathway | |||||
Noncanonical Wnt signaling pathway | |||||
Signaling events mediated by Hepatocyte Growth Factor Receptor (c-Met) | |||||
CDC42 signaling events | |||||
Thromboxane A2 receptor signaling | |||||
IL1-mediated signaling events | |||||
Role of Calcineurin-dependent NFAT signaling in lymphocytes | |||||
CXCR4-mediated signaling events | |||||
IGF1 pathway | |||||
TNF receptor signaling pathway | |||||
IL2 signaling events mediated by PI3K | |||||
Ceramide signaling pathway | |||||
p75(NTR)-mediated signaling | |||||
amb2 Integrin signaling | |||||
ErbB1 downstream signaling | |||||
Neurotrophic factor-mediated Trk receptor signaling | |||||
Nephrin/Neph1 signaling in the kidney podocyte | |||||
Insulin-mediated glucose transport | |||||
Regulation of Ras family activation | |||||
PathWhiz Pathway | Intracellular Signalling Through Adenosine Receptor A2a and Adenosine | ||||
Intracellular Signalling Through Adenosine Receptor A2b and Adenosine | |||||
Reactome | GPVI-mediated activation cascade | ||||
TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) | |||||
VEGFR2 mediated cell proliferation | |||||
WikiPathways | Calcium Regulation in the Cardiac Cell | ||||
Insulin Signaling | |||||
EGF/EGFR Signaling Pathway | |||||
Wnt Signaling Pathway | |||||
Wnt Signaling Pathway and Pluripotency | |||||
MAPK Signaling Pathway | |||||
G Protein Signaling Pathways | |||||
Myometrial Relaxation and Contraction Pathways | |||||
Signaling by TGF-beta Receptor Complex | |||||
Allograft Rejection | |||||
AGE/RAGE pathway | |||||
TNF alpha Signaling Pathway | |||||
Signaling Pathways in Glioblastoma | |||||
miRs in Muscle Cell Differentiation | |||||
IL-1 signaling pathway | |||||
GPVI-mediated activation cascade | |||||
Type II diabetes mellitus | |||||
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 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 535047 | Protein kinase C zeta isoform is critical for proliferation in human glioblastoma cell lines. J Neurooncol. 2000 Apr;47(2):109-15. |
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