Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCXD2YR)

• DOT Name: Adhesion G protein-coupled receptor L2 (ADGRL2)
• Synonyms: Calcium-independent alpha-latrotoxin receptor 2; CIRL-2; Latrophilin homolog 1; Latrophilin-2; Lectomedin-1
• Gene Name: ADGRL2
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Gastric cancer
  Microlissencephaly
  Stomach cancer
  Ankylosing spondylitis
  Autoimmune disease
  Autoimmune disease, susceptibility to, 6
  Autoimmune thyroid disease
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  Gastritis
  Isolated congenital microcephaly
  Juvenile idiopathic arthritis
  Psoriasis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic lupus erythematosus
  Type-1 diabetes
  Ulcerative colitis
  Advanced cancer
  Colon cancer
  Neoplasm
• UniProt ID: AGRL2_HUMAN
• Pfam ID: PF00002 ; PF16489 ; PF02140 ; PF01825 ; PF02793 ; PF02354 ; PF02191
• Sequence:
  MVSSGCRMRSLWFIIVISFLPNTEGFSRAALPFGLVRRELSCEGYSIDLRCPGSDVIMIE
  SANYGRTDDKICDADPFQMENTDCYLPDAFKIMTQRCNNRTQCIVVTGSDVFPDPCPGTY
  KYLEVQYECVPYIFVCPGTLKAIVDSPCIYEAEQKAGAWCKDPLQAADKIYFMPWTPYRT
  DTLIEYASLEDFQNSRQTTTYKLPNRVDGTGFVVYDGAVFFNKERTRNIVKFDLRTRIKS
  GEAIINYANYHDTSPYRWGGKTDIDLAVDENGLWVIYATEQNNGMIVISQLNPYTLRFEA
  TWETVYDKRAASNAFMICGVLYVVRSVYQDNESETGKNSIDYIYNTRLNRGEYVDVPFPN
  QYQYIAAVDYNPRDNQLYVWNNNFILRYSLEFGPPDPAQVPTTAVTITSSAELFKTIIST
  TSTTSQKGPMSTTVAGSQEGSKGTKPPPAVSTTKIPPITNIFPLPERFCEALDSKGIKWP
  QTQRGMMVERPCPKGTRGTASYLCMISTGTWNPKGPDLSNCTSHWVNQLAQKIRSGENAA
  SLANELAKHTKGPVFAGDVSSSVRLMEQLVDILDAQLQELKPSEKDSAGRSYNKLQKREK
  TCRAYLKAIVDTVDNLLRPEALESWKHMNSSEQAHTATMLLDTLEEGAFVLADNLLEPTR
  VSMPTENIVLEVAVLSTEGQIQDFKFPLGIKGAGSSIQLSANTVKQNSRNGLAKLVFIIY
  RSLGQFLSTENATIKLGADFIGRNSTIAVNSHVISVSINKESSRVYLTDPVLFTLPHIDP
  DNYFNANCSFWNYSERTMMGYWSTQGCKLVDTNKTRTTCACSHLTNFAILMAHREIAYKD
  GVHELLLTVITWVGIVISLVCLAICIFTFCFFRGLQSDRNTIHKNLCINLFIAEFIFLIG
  IDKTKYAIACPIFAGLLHFFFLAAFAWMCLEGVQLYLMLVEVFESEYSRKKYYYVAGYLF
  PATVVGVSAAIDYKSYGTEKACWLHVDNYFIWSFIGPVTFIILLNIIFLVITLCKMVKHS
  NTLKPDSSRLENIKSWVLGAFALLCLLGLTWSFGLLFINEETIVMAYLFTIFNAFQGVFI
  FIFHCALQKKVRKEYGKCFRHSYCCGGLPTESPHSSVKASTTRTSARYSSGTQSRIRRMW
  NDTVRKQSESSFISGDINSTSTLNQGMTGNYLLTNPLLRPHGTNNPYNTLLAETVVCNAP
  SAPVFNSPGHSLNNARDTSAMDTLPLNGNFNNSYSLHKGDYNDSVQVVDCGLSLNDTAFE
  KMIISELVHNNLRGSSKTHNLELTLPVKPVIGGSSSEDDAIVADASSLMHSDNPGLELHH
  KELEAPLIPQRTHSLLYQPQKKVKSEGTDSYVSQLTAEAEDHLQSPNRDSLYTSMPNLRD
  SPYPESSPDMEEDLSPSRRSENEDIYYKSMPNLGAGHQLQMCYQISRGNSDGYIIPINKE
  GCIPEGDVREGQMQLVTSL
• Function: Calcium-independent receptor of low affinity for alpha-latrotoxin, an excitatory neurotoxin present in black widow spider venom which triggers massive exocytosis from neurons and neuroendocrine cells. Receptor probably implicated in the regulation of exocytosis.
• Tissue Specificity: Expressed very widely in all normal tissues tested. Expression is variable in tumor cell lines, apparently elevated in some lines and absent or markedly reduced in others.

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[1]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Microlissencephaly	DISUCKNT	Strong	Genetic Variation	[3]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Ankylosing spondylitis	DISRC6IR	moderate	Genetic Variation	[4]
Autoimmune disease	DISORMTM	moderate	Genetic Variation	[4]
Autoimmune disease, susceptibility to, 6	DISHNUXI	moderate	Genetic Variation	[4]
Autoimmune thyroid disease	DISIHC6A	moderate	Genetic Variation	[4]
Coeliac disease	DISIY60C	moderate	Genetic Variation	[4]
Common variable immunodeficiency	DISHE7JQ	moderate	Genetic Variation	[4]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[4]
Gastritis	DIS8G07K	moderate	Genetic Variation	[5]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[6]
Juvenile idiopathic arthritis	DISQZGBV	moderate	Genetic Variation	[4]
Psoriasis	DIS59VMN	moderate	Genetic Variation	[4]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	moderate	Genetic Variation	[4]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[4]
Type-1 diabetes	DIS7HLUB	moderate	Genetic Variation	[4]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[7]
Colon cancer	DISVC52G	Limited	Biomarker	[7]
Neoplasm	DISZKGEW	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Adhesion G protein-coupled receptor L2 (ADGRL2) affects the response to substance of Methotrexate.	[19]
Fluorouracil	DMUM7HZ	Approved	Adhesion G protein-coupled receptor L2 (ADGRL2) affects the response to substance of Fluorouracil.	[19]

8 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 Adhesion G protein-coupled receptor L2 (ADGRL2).	[9]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Adhesion G protein-coupled receptor L2 (ADGRL2).	[10]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Adhesion G protein-coupled receptor L2 (ADGRL2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adhesion G protein-coupled receptor L2 (ADGRL2).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Adhesion G protein-coupled receptor L2 (ADGRL2).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Adhesion G protein-coupled receptor L2 (ADGRL2).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Adhesion G protein-coupled receptor L2 (ADGRL2).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Adhesion G protein-coupled receptor L2 (ADGRL2).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Adhesion G protein-coupled receptor L2 (ADGRL2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Adhesion G protein-coupled receptor L2 (ADGRL2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Adhesion G protein-coupled receptor L2 (ADGRL2).	[16]

References

• [1] Genomic structure and expression profile of LPHH1, a 7TM gene variably expressed in breast cancer cell lines.Biochim Biophys Acta. 2000 Apr 25;1491(1-3):75-92. doi: 10.1016/s0167-4781(00)00020-8.
• [2] CircRNA_100269 is downregulated in gastric cancer and suppresses tumor cell growth by targeting miR-630.Aging (Albany NY). 2017 Jun 27;9(6):1585-1594. doi: 10.18632/aging.101254.
• [3] Pontocerebellar hypoplasia with rhombencephalosynapsis and microlissencephaly expands the spectrum of PCH type 1B.Eur J Med Genet. 2020 Apr;63(4):103814. doi: 10.1016/j.ejmg.2019.103814. Epub 2019 Nov 23.
• [4] Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases.Nat Med. 2015 Sep;21(9):1018-27. doi: 10.1038/nm.3933. Epub 2015 Aug 24.
• [5] A preliminary study on the genetic profile of cag pathogenicity-island and other virulent gene loci of Helicobacter pylori strains from Turkey.Infect Genet Evol. 2007 Jul;7(4):509-12. doi: 10.1016/j.meegid.2007.03.002. Epub 2007 Mar 24.
• [6] A de novo variant in ADGRL2 suggests a novel mechanism underlying the previously undescribed association of extreme microcephaly with severely reduced sulcation and rhombencephalosynapsis.Acta Neuropathol Commun. 2018 Oct 19;6(1):109. doi: 10.1186/s40478-018-0610-5.
• [7] Aberrant Epigenetic Modifications of LPHN2 Function as a Potential Cisplatin-Specific Biomarker for Human Gastrointestinal Cancer.Cancer Res Treat. 2016 Apr;48(2):676-86. doi: 10.4143/crt.2015.153. Epub 2015 Sep 22.
• [8] Transcriptome and Proteome Analyses of TNFAIP8 Knockdown Cancer Cells Reveal New Insights into Molecular Determinants of Cell Survival and Tumor Progression.Methods Mol Biol. 2017;1513:83-100. doi: 10.1007/978-1-4939-6539-7_7.
• [9] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [10] 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.
• [11] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [12] 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.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.