Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZBCQ1U)

• DOT Name: Small ribosomal subunit protein RACK1 (RACK1)
• Synonyms: Cell proliferation-inducing gene 21 protein; Guanine nucleotide-binding protein subunit beta-2-like 1; Guanine nucleotide-binding protein subunit beta-like protein 12.3; Human lung cancer oncogene 7 protein; HLC-7; Receptor for activated C kinase; Receptor of activated protein C kinase 1
• Gene Name: RACK1
• Related Disease: Tourette syndrome
• UniProt ID: RACK1_HUMAN
• PDB ID: 4AOW ; 4UG0 ; 4V6X ; 5A2Q ; 5AJ0 ; 5FLX ; 5LKS ; 5OA3 ; 5T2C ; 5VYC ; 6FEC ; 6G18 ; 6G51 ; 6G53 ; 6G5H ; 6G5I ; 6IP5 ; 6IP6 ; 6IP8 ; 6OLE ; 6OLF ; 6OLG ; 6OLI ; 6OLZ ; 6OM0 ; 6OM7 ; 6QZP ; 6XA1 ; 6Y0G ; 6Y2L ; 6Y57 ; 6YBS ; 6Z6L ; 6Z6M ; 6Z6N ; 6ZLW ; 6ZM7 ; 6ZME ; 6ZMI ; 6ZMO ; 6ZMT ; 6ZMW ; 6ZN5 ; 6ZOJ ; 6ZOL ; 6ZON ; 6ZP4 ; 6ZUO ; 6ZV6 ; 6ZVH ; 6ZVJ ; 6ZXD ; 6ZXE ; 6ZXF ; 6ZXG ; 6ZXH ; 7A09 ; 7K5I ; 7QP6 ; 7QP7 ; 7R4X ; 7TQL ; 7XNX ; 7XNY ; 8G5Y ; 8G5Z ; 8G60 ; 8G61 ; 8G6J ; 8GLP ; 8JDJ ; 8JDK ; 8JDL ; 8JDM ; 8PPK ; 8PPL ; 8T4S
• Pfam ID: PF00400
• Sequence:
  MTEQMTLRGTLKGHNGWVTQIATTPQFPDMILSASRDKTIIMWKLTRDETNYGIPQRALR
  GHSHFVSDVVISSDGQFALSGSWDGTLRLWDLTTGTTTRRFVGHTKDVLSVAFSSDNRQI
  VSGSRDKTIKLWNTLGVCKYTVQDESHSEWVSCVRFSPNSSNPIIVSCGWDKLVKVWNLA
  NCKLKTNHIGHTGYLNTVTVSPDGSLCASGGKDGQAMLWDLNEGKHLYTLDGGDIINALC
  FSPNRYWLCAATGPSIKIWDLEGKIIVDELKQEVISTSSKAEPPQCTSLAWSADGQTLFA
  GYTDNLVRVWQVTIGTR
• Function: Scaffolding protein involved in the recruitment, assembly and/or regulation of a variety of signaling molecules. Interacts with a wide variety of proteins and plays a role in many cellular processes. Component of the 40S ribosomal subunit involved in translational repression. Involved in the initiation of the ribosome quality control (RQC), a pathway that takes place when a ribosome has stalled during translation, by promoting ubiquitination of a subset of 40S ribosomal subunits. Binds to and stabilizes activated protein kinase C (PKC), increasing PKC-mediated phosphorylation. May recruit activated PKC to the ribosome, leading to phosphorylation of EIF6. Inhibits the activity of SRC kinases including SRC, LCK and YES1. Inhibits cell growth by prolonging the G0/G1 phase of the cell cycle. Enhances phosphorylation of BMAL1 by PRKCA and inhibits transcriptional activity of the BMAL1-CLOCK heterodimer. Facilitates ligand-independent nuclear translocation of AR following PKC activation, represses AR transactivation activity and is required for phosphorylation of AR by SRC. Modulates IGF1R-dependent integrin signaling and promotes cell spreading and contact with the extracellular matrix. Involved in PKC-dependent translocation of ADAM12 to the cell membrane. Promotes the ubiquitination and proteasome-mediated degradation of proteins such as CLEC1B and HIF1A. Required for VANGL2 membrane localization, inhibits Wnt signaling, and regulates cellular polarization and oriented cell division during gastrulation. Required for PTK2/FAK1 phosphorylation and dephosphorylation. Regulates internalization of the muscarinic receptor CHRM2. Promotes apoptosis by increasing oligomerization of BAX and disrupting the interaction of BAX with the anti-apoptotic factor BCL2L. Inhibits TRPM6 channel activity. Regulates cell surface expression of some GPCRs such as TBXA2R. Plays a role in regulation of FLT1-mediated cell migration. Involved in the transport of ABCB4 from the Golgi to the apical bile canalicular membrane. Promotes migration of breast carcinoma cells by binding to and activating RHOA. Acts as an adapter for the dephosphorylation and inactivation of AKT1 by promoting recruitment of PP2A phosphatase to AKT1; (Microbial infection) Binds to Y.pseudotuberculosis yopK which leads to inhibition of phagocytosis and survival of bacteria following infection of host cells; (Microbial infection) Enhances phosphorylation of HIV-1 Nef by PKCs; (Microbial infection) In case of poxvirus infection, remodels the ribosomes so that they become optimal for the viral mRNAs (containing poly-A leaders) translation but not for host mRNAs; (Microbial infection) Contributes to the cap-independent internal ribosome entry site (IRES)-mediated translation by some RNA viruses.
• Tissue Specificity: In the liver, expressed at higher levels in activated hepatic stellate cells than in hepatocytes or Kupffer cells. Up-regulated in hepatocellular carcinomas and in the adjacent non-tumor liver tissue.
• KEGG Pathway: Measles (hsa05162)
• Reactome Pathway:
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  TNFR1-mediated ceramide production (R-HSA-5626978)
  Regulation of TNFR1 signaling (R-HSA-5357905)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Tourette syndrome	DISX9D54	Limited	Unknown	[1]

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 Small ribosomal subunit protein RACK1 (RACK1).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Small ribosomal subunit protein RACK1 (RACK1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Small ribosomal subunit protein RACK1 (RACK1).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Small ribosomal subunit protein RACK1 (RACK1).	[19]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Small ribosomal subunit protein RACK1 (RACK1).	[20]

24 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 Small ribosomal subunit protein RACK1 (RACK1).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[5]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[9]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Small ribosomal subunit protein RACK1 (RACK1).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[11]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Small ribosomal subunit protein RACK1 (RACK1).	[12]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[13]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[5]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Small ribosomal subunit protein RACK1 (RACK1).	[10]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[14]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[15]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[14]
Dopamine	DMPGUCF	Approved	Dopamine increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[16]
Prasterone	DM67VKL	Approved	Prasterone increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[9]
Nandrolone	DMFWKG1	Approved	Nandrolone increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[17]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[9]
G1	DMTV42K	Phase 1/2	G1 increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[21]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Small ribosomal subunit protein RACK1 (RACK1).	[22]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[23]
4-ANDROSTENE-3-17-DIONE	DMSE8NU	Investigative	4-ANDROSTENE-3-17-DIONE increases the expression of Small ribosomal subunit protein RACK1 (RACK1).	[9]

References

• [1] De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.
• [2] 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.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Effect of estrogen-active compounds on the expression of RACK1 and immunological implications. Arch Toxicol. 2020 Jun;94(6):2081-2095. doi: 10.1007/s00204-020-02756-9. Epub 2020 Apr 23.
• [6] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [7] 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.
• [8] Protein expression profiling identifies molecular targets of quercetin as a major dietary flavonoid in human colon cancer cells. Proteomics. 2004 Jul;4(7):2160-74.
• [9] Role of androgens in dhea-induced rack1 expression and cytokine modulation in monocytes. Immun Ageing. 2016 May 29;13:20. doi: 10.1186/s12979-016-0075-y. eCollection 2016.
• [10] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [11] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [12] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [13] Transcriptomic Analysis of Stem Cells Treated with Moringin or Cannabidiol: Analogies and Differences in Inflammation Pathways. Int J Mol Sci. 2019 Nov 30;20(23):6039. doi: 10.3390/ijms20236039.
• [14] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [15] Effects of endocrine disrupting chemicals on the expression of RACK1 and LPS-induced THP-1 cell activation. Toxicology. 2022 Oct;480:153321. doi: 10.1016/j.tox.2022.153321. Epub 2022 Sep 13.
• [16] Mitochondrial proteomics investigation of a cellular model of impaired dopamine homeostasis, an early step in Parkinson's disease pathogenesis. Mol Biosyst. 2014 Jun;10(6):1332-44.
• [17] The scaffold protein RACK1 is a target of endocrine disrupting chemicals (EDCs) with important implication in immunity. Toxicol Appl Pharmacol. 2017 Jun 15;325:37-47. doi: 10.1016/j.taap.2017.04.011. Epub 2017 Apr 13.
• [18] 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.
• [19] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [20] 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.
• [21] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [22] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [23] Alteration of estrogen-regulated gene expression in human cells induced by the agricultural and horticultural herbicide glyphosate. Hum Exp Toxicol. 2007 Sep;26(9):747-52. doi: 10.1177/0960327107083453.