Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase Hakai (CBLL1)
• Synonyms: EC 2.3.2.27; Casitas B-lineage lymphoma-transforming sequence-like protein 1; c-Cbl-like protein 1; RING finger protein 188; RING-type E3 ubiquitin transferase Hakai
• Gene Name: CBLL1
• Related Disease:
  Neoplasm
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Non-small-cell lung cancer
• UniProt ID: HAKAI_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF18408
• Sequence:
  MDHTDNELQGTNSSGSLGGLDVRRRIPIKLISKQANKAKPAPRTQRTINRMPAKAPPGDE
  EGFDYNEEERYDCKGGELFANQRRFPGHLFWDFQINILGEKDDTPVHFCDKCGLPIKIYG
  RMIPCKHVFCYDCAILHEKKGDKMCPGCSDPVQRIEQCTRGSLFMCSIVQGCKRTYLSQR
  DLQAHINHRHMRAGKPVTRASLENVHPPIAPPPTEIPERFIMPPDKHHMSHIPPKQHIMM
  PPPPLQHVPHEHYNQPHEDIRAPPAELSMAPPPPRSVSQETFRISTRKHSNLITVPIQDD
  SNSGAREPPPPAPAPAHHHPEYQGQPVVSHPHHIMPPQQHYAPPPPPPPPISHPMPHPPQ
  AAGTPHLVYSQAPPPPMTSAPPPITPPPGHIIAQMPPYMNHPPPGPPPPQHGGPPVTAPP
  PHHYNPNSLPQFTEDQGTLSPPFTQPGGMSPGIWPAPRGPPPPPRLQGPPSQTPLPGPHH
  PDQTRYRPYYQ
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination of several tyrosine-phosphorylated Src substrates, including CDH1, CTTN and DOK1. Targets CDH1 for endocytosis and degradation. Associated component of the WMM complex, a complex that mediates N6-methyladenosine (m6A) methylation of RNAs, a modification that plays a role in the efficiency of mRNA splicing and RNA processing. Its function in the WMM complex is unknown.
• Reactome Pathway: InlA-mediated entry of Listeria monocytogenes into host cells (R-HSA-8876493)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Colon cancer	DISVC52G	Strong	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[2]

10 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 Hakai (CBLL1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[10]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase Hakai (CBLL1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase Hakai (CBLL1).	[8]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of E3 ubiquitin-protein ligase Hakai (CBLL1).	[13]

References

• [1] CBLL1 is highly expressed in non-small cell lung cancer and promotes cell proliferation and invasion.Thorac Cancer. 2019 Jun;10(6):1479-1488. doi: 10.1111/1759-7714.13097. Epub 2019 May 23.
• [2] Downregulation of long non-coding RNA XIST inhibits cell proliferation, migration, invasion and EMT by regulating miR-212-3p/CBLL1 axis in non-small cell lung cancer cells.Eur Rev Med Pharmacol Sci. 2019 Oct;23(19):8391-8402. doi: 10.26355/eurrev_201910_19150.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] 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.
• [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] 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.
• [8] 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.
• [9] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.