Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3Y21AF)

• DOT Name: Casein kinase I isoform gamma-2 (CSNK1G2)
• Synonyms: CKI-gamma 2; EC 2.7.11.1
• Gene Name: CSNK1G2
• UniProt ID: KC1G2_HUMAN
• PDB ID: 2C47
• EC Number: 2.7.11.1
• Pfam ID: PF12605 ; PF00069
• Sequence:
  MDFDKKGGKGETEEGRRMSKAGGGRSSHGIRSSGTSSGVLMVGPNFRVGKKIGCGNFGEL
  RLGKNLYTNEYVAIKLEPIKSRAPQLHLEYRFYKQLSATEGVPQVYYFGPCGKYNAMVLE
  LLGPSLEDLFDLCDRTFTLKTVLMIAIQLITRMEYVHTKSLIYRDVKPENFLVGRPGTKR
  QHAIHIIDFGLAKEYIDPETKKHIPYREHKSLTGTARYMSINTHLGKEQSRRDDLEALGH
  MFMYFLRGSLPWQGLKADTLKERYQKIGDTKRATPIEVLCENFPEEMATYLRYVRRLDFF
  EKPDYDYLRKLFTDLFDRSGFVFDYEYDWAGKPLPTPIGTVHTDLPSQPQLRDKTQPHSK
  NQALNSTNGELNADDPTAGHSNAPITAPAEVEVADETKCCCFFKRRKRKSLQRHK
• Function: Serine/threonine-protein kinase. Casein kinases are operationally defined by their preferential utilization of acidic proteins such as caseins as substrates. It can phosphorylate a large number of proteins. Participates in Wnt signaling. Phosphorylates COL4A3BP/CERT, MTA1 and SMAD3. SMAD3 phosphorylation promotes its ligand-dependent ubiquitination and subsequent proteasome degradation, thus inhibiting SMAD3-mediated TGF-beta responses. Hyperphosphorylation of the serine-repeat motif of COL4A3BP/CERT leads to its inactivation by dissociation from the Golgi complex, thus down-regulating ER-to-Golgi transport of ceramide and sphingomyelin synthesis. Triggers PER1 proteasomal degradation probably through phosphorylation. Involved in brain development and vesicular trafficking and neurotransmitter releasing from small synaptic vesicles. Regulates fast synaptic transmission mediated by glutamate. Involved in regulation of reactive oxygen species (ROS) levels.
• Tissue Specificity: Testis.
• KEGG Pathway: Hedgehog sig.ling pathway (hsa04340)
• Reactome Pathway:
  Disassembly of the destruction complex and recruitment of AXIN to the membrane (R-HSA-4641262)
  Sphingolipid de novo biosynthesis (R-HSA-1660661)

Molecular Interaction Atlas (MIA) of This DOT

4 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 Casein kinase I isoform gamma-2 (CSNK1G2).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Casein kinase I isoform gamma-2 (CSNK1G2).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Casein kinase I isoform gamma-2 (CSNK1G2).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Casein kinase I isoform gamma-2 (CSNK1G2).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Casein kinase I isoform gamma-2 (CSNK1G2).	[2]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Casein kinase I isoform gamma-2 (CSNK1G2).	[4]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Casein kinase I isoform gamma-2 (CSNK1G2).	[5]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Casein kinase I isoform gamma-2 (CSNK1G2).	[7]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Casein kinase I isoform gamma-2 (CSNK1G2).	[4]

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] 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.
• [3] 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.
• [4] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [5] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [6] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [7] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [8] 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.