Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase CBL (CBL)
• Synonyms: EC 2.3.2.27; Casitas B-lineage lymphoma proto-oncogene; Proto-oncogene c-Cbl; RING finger protein 55; RING-type E3 ubiquitin transferase CBL; Signal transduction protein CBL
• Gene Name: CBL
• Related Disease:
  CBL-related disorder
  Chronic myelomonocytic leukaemia
  Noonan syndrome
• UniProt ID: CBL_HUMAN
• PDB ID: 1B47; 1FBV; 1YVH; 2CBL; 2JUJ; 2K4D; 2OO9; 2Y1M; 2Y1N; 3BUM; 3BUN; 3BUO; 3BUW; 3BUX; 3OB1; 3OB2; 3PLF; 4A49; 4A4B; 4A4C; 4GPL; 5HKW; 5HKX; 5HKY; 5HKZ; 5HL0; 5J3X; 5O76; 6O02; 6O03; 6XAR; 7SIY
• EC Number: 2.3.2.27
• Pfam ID: PF02262 ; PF02761 ; PF02762 ; PF00627 ; PF00097
• Sequence:
  MAGNVKKSSGAGGGSGSGGSGSGGLIGLMKDAFQPHHHHHHHLSPHPPGTVDKKMVEKCW
  KLMDKVVRLCQNPKLALKNSPPYILDLLPDTYQHLRTILSRYEGKMETLGENEYFRVFME
  NLMKKTKQTISLFKEGKERMYEENSQPRRNLTKLSLIFSHMLAELKGIFPSGLFQGDTFR
  ITKADAAEFWRKAFGEKTIVPWKSFRQALHEVHPISSGLEAMALKSTIDLTCNDYISVFE
  FDIFTRLFQPWSSLLRNWNSLAVTHPGYMAFLTYDEVKARLQKFIHKPGSYIFRLSCTRL
  GQWAIGYVTADGNILQTIPHNKPLFQALIDGFREGFYLFPDGRNQNPDLTGLCEPTPQDH
  IKVTQEQYELYCEMGSTFQLCKICAENDKDVKIEPCGHLMCTSCLTSWQESEGQGCPFCR
  CEIKGTEPIVVDPFDPRGSGSLLRQGAEGAPSPNYDDDDDERADDTLFMMKELAGAKVER
  PPSPFSMAPQASLPPVPPRLDLLPQRVCVPSSASALGTASKAASGSLHKDKPLPVPPTLR
  DLPPPPPPDRPYSVGAESRPQRRPLPCTPGDCPSRDKLPPVPSSRLGDSWLPRPIPKVPV
  SAPSSSDPWTGRELTNRHSLPFSLPSQMEPRPDVPRLGSTFSLDTSMSMNSSPLVGPECD
  HPKIKPSSSANAIYSLAARPLPVPKLPPGEQCEGEEDTEYMTPSSRPLRPLDTSQSSRAC
  DCDQQIDSCTYEAMYNIQSQAPSITESSTFGEGNLAAAHANTGPEESENEDDGYDVPKPP
  VPAVLARRTLSDISNASSSFGWLSLDGDPTTNVTEGSQVPERPPKPFPRRINSERKAGSC
  QQGSGPAASAATASPQLSSEIENLMSQGYSYQDIQKALVIAQNNIEMAKNILREFVSISS
  PAHVAT
• Function: Adapter protein that functions as a negative regulator of many signaling pathways that are triggered by activation of cell surface receptors. Acts as an E3 ubiquitin-protein ligase, which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their degradation by the proteasome. Ubiquitinates SPRY2. Ubiquitinates EGFR. Recognizes activated receptor tyrosine kinases, including KIT, FLT1, FGFR1, FGFR2, PDGFRA, PDGFRB, CSF1R, EPHA8 and KDR and terminates signaling. Recognizes membrane-bound HCK, SRC and other kinases of the SRC family and mediates their ubiquitination and degradation. Participates in signal transduction in hematopoietic cells. Plays an important role in the regulation of osteoblast differentiation and apoptosis. Essential for osteoclastic bone resorption. The 'Tyr-731' phosphorylated form induces the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. May be functionally coupled with the E2 ubiquitin-protein ligase UB2D3. In association with CBLB, required for proper feedback inhibition of ciliary platelet-derived growth factor receptor-alpha (PDGFRA) signaling pathway via ubiquitination and internalization of PDGFRA.
• KEGG Pathway:
  ErbB sig.ling pathway (hsa04012)
  Ubiquitin mediated proteolysis (hsa04120)
  Endocytosis (hsa04144)
  Insulin sig.ling pathway (hsa04910)
  Bacterial invasion of epithelial cells (hsa05100)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Chronic myeloid leukemia (hsa05220)
• Reactome Pathway:
  Constitutive Signaling by Ligand-Responsive EGFR Cancer Variants (R-HSA-1236382)
  Spry regulation of FGF signaling (R-HSA-1295596)
  Regulation of KIT signaling (R-HSA-1433559)
  EGFR downregulation (R-HSA-182971)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  Constitutive Signaling by EGFRvIII (R-HSA-5637810)
  Negative regulation of FGFR1 signaling (R-HSA-5654726)
  Negative regulation of FGFR2 signaling (R-HSA-5654727)
  Negative regulation of FGFR3 signaling (R-HSA-5654732)
  Negative regulation of FGFR4 signaling (R-HSA-5654733)
  Negative regulation of MET activity (R-HSA-6807004)
  PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 (R-HSA-8849469)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Clathrin-mediated endocytosis (R-HSA-8856828)
  InlB-mediated entry of Listeria monocytogenes into host cell (R-HSA-8875360)
  Regulation of signaling by CBL (R-HSA-912631)
  Signaling by CSF1 (M-CSF) in myeloid cells (R-HSA-9680350)
  Negative regulation of FLT3 (R-HSA-9706369)
  FLT3 signaling by CBL mutants (R-HSA-9706377)
  Interleukin-6 signaling (R-HSA-1059683)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
CBL-related disorder	DISY9Q92	Definitive	Autosomal dominant	[1]
Chronic myelomonocytic leukaemia	DISDN5P7	Strong	Autosomal dominant	[2]
Noonan syndrome	DIS7Q7DN	Supportive	Autosomal dominant	[3]

21 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 E3 ubiquitin-protein ligase CBL (CBL).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[12]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of E3 ubiquitin-protein ligase CBL (CBL).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[15]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of E3 ubiquitin-protein ligase CBL (CBL).	[14]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[16]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[18]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[16]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[21]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase CBL (CBL).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of E3 ubiquitin-protein ligase CBL (CBL).	[20]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Germline CBL mutations cause developmental abnormalities and predispose to juvenile myelomonocytic leukemia. Nat Genet. 2010 Sep;42(9):794-800. doi: 10.1038/ng.641. Epub 2010 Aug 8.
• [3] Molecular Diversity and Associated Phenotypic Spectrum of Germline CBL Mutations. Hum Mutat. 2015 Aug;36(8):787-96. doi: 10.1002/humu.22809. Epub 2015 Jun 1.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [10] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [11] 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.
• [12] Arsenic trioxide induces apoptosis and G2/M phase arrest by inducing Cbl to inhibit PI3K/Akt signaling and thereby regulate p53 activation. Cancer Lett. 2009 Nov 1;284(2):208-15. doi: 10.1016/j.canlet.2009.04.035. Epub 2009 May 19.
• [13] 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.
• [14] 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.
• [15] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [16] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [17] 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.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] Resveratrol induces apoptosis and alters gene expression in human fibrosarcoma cells. Anticancer Res. 2015 Feb;35(2):767-74.
• [20] 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.
• [21] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [22] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [23] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.