Target General Infomation
Target ID
T74258
Former ID
TTDR01403
Target Name
mRNA of PKC-zeta
Gene Name
PRKCZ
Synonyms
PRKCZ (mRNA); nPKC-zeta (mRNA); PRKCZ
Target Type
Discontinued
Function
Calcium- and diacylglycerol-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, functionsdownstream 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 thana 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.
BioChemical Class
Kinase
Target Validation
T74258
UniProt ID
EC Number
EC 2.7.11.13
Sequence
MPSRTGPKMEGSGGRVRLKAHYGGDIFITSVDAATTFEELCEEVRDMCRLHQQHPLTLKW
VDSEGDPCTVSSQMELEEAFRLARQCRDEGLIIHVFPSTPEQPGLPCPGEDKSIYRRGAR
RWRKLYRANGHLFQAKRFNRRAYCGQCSERIWGLARQGYRCINCKLLVHKRCHGLVPLTC
RKHMDSVMPSQEPPVDDKNEDADLPSEETDGIAYISSSRKHDSIKDDSEDLKPVIDGMDG
IKISQGLGLQDFDLIRVIGRGSYAKVLLVRLKKNDQIYAMKVVKKELVHDDEDIDWVQTE
KHVFEQASSNPFLVGLHSCFQTTSRLFLVIEYVNGGDLMFHMQRQRKLPEEHARFYAAEI
CIALNFLHERGIIYRDLKLDNVLLDADGHIKLTDYGMCKEGLGPGDTTSTFCGTPNYIAP
EILRGEEYGFSVDWWALGVLMFEMMAGRSPFDIITDNPDMNTEDYLFQVILEKPIRIPRF
LSVKASHVLKGFLNKDPKERLGCRPQTGFSDIKSHAFFRSIDWDLLEKKQALPPFQPQIT
DDYGLDNFDTQFTSEPVQLTPDDEDAIKRIDQSEFEGFEYINPLLLSTEESV
Drugs and Mode of Action
Drug(s) BALANOL Drug Info Terminated Discovery agent [542983], [545589]
Inhibitor BALANOL Drug Info [551285]
compound 3 Drug Info [529880]
Go 6983 Drug Info [534191]
LY-326449 Drug Info [534154]
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 542983(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: 8142).
Ref 545589Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003814)
Ref 5298802-(6-Phenyl-1H-indazol-3-yl)-1H-benzo[d]imidazoles: design and synthesis of a potent and isoform selective PKC-zeta inhibitor. Bioorg Med Chem Lett. 2009 Feb 1;19(3):908-11.
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 534191Inhibition of protein kinase C mu by various inhibitors. Differentiation from protein kinase c isoenzymes. FEBS Lett. 1996 Aug 26;392(2):77-80.
Ref 549607US patent application no. 5,959,096, Antisense oligonucleotides against human protein kinase C.
Ref 551285Evaluation of differential hypoxic cytotoxicity and electrochemical studies of nitro 5-deazaflavins, Bioorg. Med. Chem. Lett. 5(18):2155-2160 (1995).

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