Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPLRER9)

• DOT Name: E3 ubiquitin-protein ligase CBL-B (CBLB)
• Synonyms: EC 2.3.2.27; Casitas B-lineage lymphoma proto-oncogene b; RING finger protein 56; RING-type E3 ubiquitin transferase CBL-B; SH3-binding protein CBL-B; Signal transduction protein CBL-B
• Gene Name: CBLB
• Related Disease: Autoimmune disease, multisystem, infantile-onset, 3
• UniProt ID: CBLB_HUMAN
• PDB ID: 2AK5; 2BZ8; 2DO6; 2J6F; 2JNH; 2LDR; 2OOA; 2OOB; 3PFV; 3VGO; 3ZNI; 8GCY; 8QNG; 8QNH; 8QNI
• EC Number: 2.3.2.27
• Pfam ID: PF02262 ; PF02761 ; PF02762 ; PF00097
• Sequence:
  MANSMNGRNPGGRGGNPRKGRILGIIDAIQDAVGPPKQAAADRRTVEKTWKLMDKVVRLC
  QNPKLQLKNSPPYILDILPDTYQHLRLILSKYDDNQKLAQLSENEYFKIYIDSLMKKSKR
  AIRLFKEGKERMYEEQSQDRRNLTKLSLIFSHMLAEIKAIFPNGQFQGDNFRITKADAAE
  FWRKFFGDKTIVPWKVFRQCLHEVHQISSGLEAMALKSTIDLTCNDYISVFEFDIFTRLF
  QPWGSILRNWNFLAVTHPGYMAFLTYDEVKARLQKYSTKPGSYIFRLSCTRLGQWAIGYV
  TGDGNILQTIPHNKPLFQALIDGSREGFYLYPDGRSYNPDLTGLCEPTPHDHIKVTQEQY
  ELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTAWQESDGQGCPFCRCEIKGTEP
  IIVDPFDPRDEGSRCCSIIDPFGMPMLDLDDDDDREESLMMNRLANVRKCTDRQNSPVTS
  PGSSPLAQRRKPQPDPLQIPHLSLPPVPPRLDLIQKGIVRSPCGSPTGSPKSSPCMVRKQ
  DKPLPAPPPPLRDPPPPPPERPPPIPPDNRLSRHIHHVESVPSRDPPMPLEAWCPRDVFG
  TNQLVGCRLLGEGSPKPGITASSNVNGRHSRVGSDPVLMRKHRRHDLPLEGAKVFSNGHL
  GSEEYDVPPRLSPPPPVTTLLPSIKCTGPLANSLSEKTRDPVEEDDDEYKIPSSHPVSLN
  SQPSHCHNVKPPVRSCDNGHCMLNGTHGPSSEKKSNIPDLSIYLKGDVFDSASDPVPLPP
  ARPPTRDNPKHGSSLNRTPSDYDLLIPPLGEDAFDALPPSLPPPPPPARHSLIEHSKPPG
  SSSRPSSGQDLFLLPSDPFVDLASGQVPLPPARRLPGENVKTNRTSQDYDQLPSCSDGSQ
  APARPPKPRPRRTAPEIHHRKPHGPEAALENVDAKIAKLMGEGYAFEEVKRALEIAQNNV
  EVARSILREFAFPPPVSPRLNL
• Function: E3 ubiquitin-protein ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and transfers it to substrates, generally promoting their degradation by the proteasome. Negatively regulates TCR (T-cell receptor), BCR (B-cell receptor) and FCER1 (high affinity immunoglobulin epsilon receptor) signal transduction pathways. In naive T-cells, inhibits VAV1 activation upon TCR engagement and imposes a requirement for CD28 costimulation for proliferation and IL-2 production. Also acts by promoting PIK3R1/p85 ubiquitination, which impairs its recruitment to the TCR and subsequent activation. In activated T-cells, inhibits PLCG1 activation and calcium mobilization upon restimulation and promotes anergy. In B-cells, acts by ubiquitinating SYK and promoting its proteasomal degradation. Slightly promotes SRC ubiquitination. May be involved in EGFR ubiquitination and internalization. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBL, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA.
• Tissue Specificity: Expressed in placenta, heart, lung, kidney, spleen, ovary and testis, as well as fetal brain and liver and hematopoietic cell lines, but not in adult brain, liver, pancreas, salivary gland, or skeletal muscle. Present in lymphocytes (at protein level).
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Ubiquitin mediated proteolysis (hsa04120)
  Endocytosis (hsa04144)
  C-type lectin receptor sig.ling pathway (hsa04625)
  T cell receptor sig.ling pathway (hsa04660)
  Insulin sig.ling pathway (hsa04910)
  Measles (hsa05162)
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autoimmune disease, multisystem, infantile-onset, 3	DIS0EB4Z	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[10]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[11]
Selenium	DM25CGV	Approved	Selenium decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[12]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[13]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[15]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[21]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[22]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[24]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[25]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[26]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of E3 ubiquitin-protein ligase CBL-B (CBLB).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of E3 ubiquitin-protein ligase CBL-B (CBLB).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase CBL-B (CBLB).	[20]

References

• [1] c-Cbl-mediated regulation of LAT-nucleated signaling complexes. Mol Cell Biol. 2007 Dec;27(24):8622-36. doi: 10.1128/MCB.00467-07. Epub 2007 Oct 15.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [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] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Epidermal growth factor receptor signalling in human breast cancer cells operates parallel to estrogen receptor alpha signalling and results in tamoxifen insensitive proliferation. BMC Cancer. 2014 Apr 23;14:283.
• [8] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [9] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [10] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [11] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [12] 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.
• [13] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Epigallocatechin-3-gallate (EGCG) protects against chromate-induced toxicity in vitro. Toxicol Appl Pharmacol. 2012 Jan 15;258(2):166-75.
• [16] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [17] BET bromodomain inhibition as a novel strategy for reactivation of HIV-1. J Leukoc Biol. 2012 Dec;92(6):1147-54. doi: 10.1189/jlb.0312165. Epub 2012 Jul 16.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [22] Identification of gene markers for formaldehyde exposure in humans. Environ Health Perspect. 2007 Oct;115(10):1460-6. doi: 10.1289/ehp.10180.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [26] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [27] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.