Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN2FE42)

• DOT Name: Protein kinase C zeta type (PRKCZ)
• Synonyms: EC 2.7.11.13; nPKC-zeta
• Gene Name: PRKCZ
• UniProt ID: KPCZ_HUMAN
• EC Number: 2.7.11.13
• Pfam ID: PF00130 ; PF00564 ; PF00069 ; PF00433
• Sequence:
  MPSRTGPKMEGSGGRVRLKAHYGGDIFITSVDAATTFEELCEEVRDMCRLHQQHPLTLKW
  VDSEGDPCTVSSQMELEEAFRLARQCRDEGLIIHVFPSTPEQPGLPCPGEDKSIYRRGAR
  RWRKLYRANGHLFQAKRFNRRAYCGQCSERIWGLARQGYRCINCKLLVHKRCHGLVPLTC
  RKHMDSVMPSQEPPVDDKNEDADLPSEETDGIAYISSSRKHDSIKDDSEDLKPVIDGMDG
  IKISQGLGLQDFDLIRVIGRGSYAKVLLVRLKKNDQIYAMKVVKKELVHDDEDIDWVQTE
  KHVFEQASSNPFLVGLHSCFQTTSRLFLVIEYVNGGDLMFHMQRQRKLPEEHARFYAAEI
  CIALNFLHERGIIYRDLKLDNVLLDADGHIKLTDYGMCKEGLGPGDTTSTFCGTPNYIAP
  EILRGEEYGFSVDWWALGVLMFEMMAGRSPFDIITDNPDMNTEDYLFQVILEKPIRIPRF
  LSVKASHVLKGFLNKDPKERLGCRPQTGFSDIKSHAFFRSIDWDLLEKKQALPPFQPQIT
  DDYGLDNFDTQFTSEPVQLTPDDEDAIKRIDQSEFEGFEYINPLLLSTEESV
• 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, 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'. Phosphorylates VAMP2 in vitro ; [Isoform 2]: Involved in late synaptic long term potention phase in CA1 hippocampal cells and long term memory maintenance.
• Tissue Specificity: Expressed in brain, and to a lesser extent in lung, kidney and testis.
• KEGG Pathway:
  Rap1 sig.ling pathway (hsa04015)
  Chemokine sig.ling pathway (hsa04062)
  Sphingolipid sig.ling pathway (hsa04071)
  Endocytosis (hsa04144)
  Axon guidance (hsa04360)
  Hippo sig.ling pathway (hsa04390)
  Tight junction (hsa04530)
  Platelet activation (hsa04611)
  Insulin sig.ling pathway (hsa04910)
  Relaxin sig.ling pathway (hsa04926)
  Type II diabetes mellitus (hsa04930)
  Insulin resistance (hsa04931)
  AGE-RAGE sig.ling pathway in diabetic complications (hsa04933)
  Human papillomavirus infection (hsa05165)
  Diabetic cardiomyopathy (hsa05415)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) (R-HSA-2173791)
  VEGFR2 mediated cell proliferation (R-HSA-5218921)
  RHO GTPases Activate NADPH Oxidases (R-HSA-5668599)
  Estrogen-stimulated signaling through PRKCZ (R-HSA-9634635)
  GPVI-mediated activation cascade (R-HSA-114604)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Protein kinase C zeta type (PRKCZ) affects the response to substance of Arsenic trioxide.	[18]
Cytarabine	DMZD5QR	Approved	Protein kinase C zeta type (PRKCZ) decreases the response to substance of Cytarabine.	[19]
Etoposide	DMNH3PG	Approved	Protein kinase C zeta type (PRKCZ) increases the response to substance of Etoposide.	[19]
Daunorubicin	DMQUSBT	Approved	Protein kinase C zeta type (PRKCZ) decreases the response to substance of Daunorubicin.	[19]
Deoxycholic acid	DM3GYAL	Approved	Protein kinase C zeta type (PRKCZ) decreases the response to substance of Deoxycholic acid.	[20]
Afimoxifene	DMFORDT	Phase 2	Protein kinase C zeta type (PRKCZ) decreases the response to substance of Afimoxifene.	[21]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Protein kinase C zeta type (PRKCZ).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein kinase C zeta type (PRKCZ).	[5]
LY294002	DMY1AFS	Phase 1	LY294002 decreases the phosphorylation of Protein kinase C zeta type (PRKCZ).	[14]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein kinase C zeta type (PRKCZ).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein kinase C zeta type (PRKCZ).	[17]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein kinase C zeta type (PRKCZ).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein kinase C zeta type (PRKCZ).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein kinase C zeta type (PRKCZ).	[4]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Protein kinase C zeta type (PRKCZ).	[6]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein kinase C zeta type (PRKCZ).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Protein kinase C zeta type (PRKCZ).	[8]
Nicotine	DMWX5CO	Approved	Nicotine increases the activity of Protein kinase C zeta type (PRKCZ).	[9]
Carbachol	DMX9K8F	Approved	Carbachol increases the activity of Protein kinase C zeta type (PRKCZ).	[11]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Protein kinase C zeta type (PRKCZ).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein kinase C zeta type (PRKCZ).	[13]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 increases the expression of Protein kinase C zeta type (PRKCZ).	[15]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the cleavage of Protein kinase C zeta type (PRKCZ).	[10]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [6] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [7] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [8] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [9] Protein kinase Czeta abrogates the proapoptotic function of Bax through phosphorylation. J Biol Chem. 2007 Jul 20;282(29):21268-77. doi: 10.1074/jbc.M701613200. Epub 2007 May 24.
• [10] Mitomycin C induces apoptosis in a caspases-dependent and Fas/CD95-independent manner in human gastric adenocarcinoma cells. Cancer Lett. 2000 Oct 1;158(2):125-32. doi: 10.1016/s0304-3835(00)00489-4.
• [11] Role of phospholipase D signaling in ethanol-induced inhibition of carbachol-stimulated DNA synthesis of 1321N1 astrocytoma cells. J Neurochem. 2004 Aug;90(3):646-53. doi: 10.1111/j.1471-4159.2004.02541.x.
• [12] Regulation of IL-1-induced selective IL-6 release from human mast cells and inhibition by quercetin. Br J Pharmacol. 2006 May;148(2):208-15. doi: 10.1038/sj.bjp.0706695.
• [13] Comparative mechanisms of PAH toxicity by benzo[a]pyrene and dibenzo[def,p]chrysene in primary human bronchial epithelial cells cultured at air-liquid interface. Toxicol Appl Pharmacol. 2019 Sep 15;379:114644.
• [14] A new selective AKT pharmacological inhibitor reduces resistance to chemotherapeutic drugs, TRAIL, all-trans-retinoic acid, and ionizing radiation of human leukemia cells. Leukemia. 2003 Sep;17(9):1794-805. doi: 10.1038/sj.leu.2403044.
• [15] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.
• [16] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Characterization of arsenic trioxide resistant clones derived from Jurkat leukemia T cell line: focus on PI3K/Akt signaling pathway. Chem Biol Interact. 2013 Oct 5;205(3):198-211. doi: 10.1016/j.cbi.2013.07.011. Epub 2013 Aug 2.
• [19] 4-benzimidazolyl-3-phenylbutanoic acids as novel PIF-pocket-targeting allosteric inhibitors of protein kinase PKC. J Med Chem. 2011 Oct 13;54(19):6714-23. doi: 10.1021/jm2005892. Epub 2011 Sep 14.
• [20] Development and molecular characterization of HCT-116 cell lines resistant to the tumor promoter and multiple stress-inducer, deoxycholate. Carcinogenesis. 2002 Dec;23(12):2063-80. doi: 10.1093/carcin/23.12.2063.
• [21] High-throughput ectopic expression screen for tamoxifen resistance identifies an atypical kinase that blocks autophagy. Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2058-63.