Details of Drug Off-Target (DOT)

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

• DOT Name: E3 ubiquitin-protein ligase LNX (LNX1)
• Synonyms: EC 2.3.2.27; Ligand of Numb-protein X 1; Numb-binding protein 1; PDZ domain-containing RING finger protein 2; RING-type E3 ubiquitin transferase LNX
• Gene Name: LNX1
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Nervous system neoplasm
  Uterine fibroids
  Acute myelogenous leukaemia
• UniProt ID: LNX1_HUMAN
• PDB ID: 3B76; 5H7R; 5H7S
• EC Number: 2.3.2.27
• Pfam ID: PF00595 ; PF00097
• Sequence:
  MNQPESANDPEPLCAVCGQAHSLEENHFYSYPEEVDDDLICHICLQALLDPLDTPCGHTY
  CTLCLTNFLVEKDFCPMDRKPLVLQHCKKSSILVNKLLNKLLVTCPFREHCTQVLQRCDL
  EHHFQTSCKGASHYGLTKDRKRRSQDGCPDGCASLTATAPSPEVSAAATISLMTDEPGLD
  NPAYVSSAEDGQPAISPVDSGRSNRTRARPFERSTIRSRSFKKINRALSVLRRTKSGSAV
  ANHADQGRENSENTTAPEVFPRLYHLIPDGEITSIKINRVDPSESLSIRLVGGSETPLVH
  IIIQHIYRDGVIARDGRLLPGDIILKVNGMDISNVPHNYAVRLLRQPCQVLWLTVMREQK
  FRSRNNGQAPDAYRPRDDSFHVILNKSSPEEQLGIKLVRKVDEPGVFIFNVLDGGVAYRH
  GQLEENDRVLAINGHDLRYGSPESAAHLIQASERRVHLVVSRQVRQRSPDIFQEAGWNSN
  GSWSPGPGERSNTPKPLHPTITCHEKVVNIQKDPGESLGMTVAGGASHREWDLPIYVISV
  EPGGVISRDGRIKTGDILLNVDGVELTEVSRSEAVALLKRTSSSIVLKALEVKEYEPQED
  CSSPAALDSNHNMAPPSDWSPSWVMWLELPRCLYNCKDIVLRRNTAGSLGFCIVGGYEEY
  NGNKPFFIKSIVEGTPAYNDGRIRCGDILLAVNGRSTSGMIHACLARLLKELKGRITLTI
  VSWPGTFL
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of NUMB. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates ubiquitination of isoform p66 and isoform p72 of NUMB, but not that of isoform p71 or isoform p65; Isoform 2 provides an endocytic scaffold for IGSF5/JAM4.
• Tissue Specificity: Expressed in heart, placenta, kidney, pancreas and brain.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Genetic Variation	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Nervous system neoplasm	DIS141UP	Strong	Biomarker	[3]
Uterine fibroids	DISBZRMJ	Strong	Genetic Variation	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of E3 ubiquitin-protein ligase LNX (LNX1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase LNX (LNX1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of E3 ubiquitin-protein ligase LNX (LNX1).	[11]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of E3 ubiquitin-protein ligase LNX (LNX1).	[13]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of E3 ubiquitin-protein ligase LNX (LNX1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of E3 ubiquitin-protein ligase LNX (LNX1).	[16]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of E3 ubiquitin-protein ligase LNX (LNX1).	[17]

3 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 LNX (LNX1).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of E3 ubiquitin-protein ligase LNX (LNX1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of E3 ubiquitin-protein ligase LNX (LNX1).	[15]

References

• [1] Suppression of cancer stemness by upregulating Ligand-of-Numb protein X1 in colorectal carcinoma.PLoS One. 2017 Nov 30;12(11):e0188665. doi: 10.1371/journal.pone.0188665. eCollection 2017.
• [2] Characterization of the amplicon on chromosomal segment 4q12 in glioblastoma multiforme.Neuro Oncol. 2007 Jul;9(3):291-7. doi: 10.1215/15228517-2007-009. Epub 2007 May 15.
• [3] Mutation and copy number analysis of LNX1 and Numbl in nervous system tumors.Cancer Genet Cytogenet. 2008 Oct 15;186(2):103-9. doi: 10.1016/j.cancergencyto.2008.07.003.
• [4] PDZRN4 acts as a suppressor of cell proliferation in human liver cancer cell lines.Cell Biochem Funct. 2015 Oct;33(7):443-9. doi: 10.1002/cbf.3130. Epub 2015 Oct 20.
• [5] Novel STAT3 Inhibitor LDOC1 Targets Phospho-JAK2 for Degradation by Interacting with LNX1 and Regulates the Aggressiveness of Lung Cancer.Cancers (Basel). 2019 Jan 9;11(1):63. doi: 10.3390/cancers11010063.
• [6] LNX1 contributes to tumor growth by down-regulating p53 stability.FASEB J. 2019 Dec;33(12):13216-13227. doi: 10.1096/fj.201900366R. Epub 2019 Sep 18.
• [7] Genome-wide association and epidemiological analyses reveal common genetic origins between uterine leiomyomata and endometriosis.Nat Commun. 2019 Oct 24;10(1):4857. doi: 10.1038/s41467-019-12536-4.
• [8] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [9] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [14] 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.
• [15] 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.
• [16] 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.
• [17] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.