Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN1GAG7)

• DOT Name: Adhesion G protein-coupled receptor L4 (ADGRL4)
• Synonyms: EGF, latrophilin and seven transmembrane domain-containing protein 1; EGF-TM7-latrophilin-related protein; ETL protein
• Gene Name: ADGRL4
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Cardiac disease
  Glioblastoma multiforme
  Glioma
  Kidney failure
  Neoplasm
  Graft-versus-host disease
  Hepatocellular carcinoma
• UniProt ID: AGRL4_HUMAN
• Pfam ID: PF00002 ; PF07645 ; PF16489 ; PF01825
• Sequence:
  MKRLPLLVVFSTLLNCSYTQNCTKTPCLPNAKCEIRNGIEACYCNMGFSGNGVTICEDDN
  ECGNLTQSCGENANCTNTEGSYYCMCVPGFRSSSNQDRFITNDGTVCIENVNANCHLDNV
  CIAANINKTLTKIRSIKEPVALLQEVYRNSVTDLSPTDIITYIEILAESSSLLGYKNNTI
  SAKDTLSNSTLTEFVKTVNNFVQRDTFVVWDKLSVNHRRTHLTKLMHTVEQATLRISQSF
  QKTTEFDTNSTDIALKVFFFDSYNMKHIHPHMNMDGDYINIFPKRKAAYDSNGNVAVAFV
  YYKSIGPLLSSSDNFLLKPQNYDNSEEEERVISSVISVSMSSNPPTLYELEKITFTLSHR
  KVTDRYRSLCAFWNYSPDTMNGSWSSEGCELTYSNETHTSCRCNHLTHFAILMSSGPSIG
  IKDYNILTRITQLGIIISLICLAICIFTFWFFSEIQSTRTTIHKNLCCSLFLAELVFLVG
  INTNTNKLFCSIIAGLLHYFFLAAFAWMCIEGIHLYLIVVGVIYNKGFLHKNFYIFGYLS
  PAVVVGFSAALGYRYYGTTKVCWLSTENNFIWSFIGPACLIILVNLLAFGVIIYKVFRHT
  AGLKPEVSCFENIRSCARGALALLFLLGTTWIFGVLHVVHASVVTAYLFTVSNAFQGMFI
  FLFLCVLSRKIQEEYYRLFKNVPCCFGCLR
• Function: Endothelial orphan receptor that acts as a key regulator of angiogenesis.
• Tissue Specificity: Detected in the majority of epithelial cells in tumor and normal tissues. Expressed also in human umbilical vein endothelial cells.

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cardiac disease	DISVO1I5	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Kidney failure	DISOVQ9P	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Graft-versus-host disease	DIS0QADF	moderate	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[7]

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 Adhesion G protein-coupled receptor L4 (ADGRL4).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Adhesion G protein-coupled receptor L4 (ADGRL4).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Adhesion G protein-coupled receptor L4 (ADGRL4).	[10]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Adhesion G protein-coupled receptor L4 (ADGRL4).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Adhesion G protein-coupled receptor L4 (ADGRL4).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Adhesion G protein-coupled receptor L4 (ADGRL4).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Adhesion G protein-coupled receptor L4 (ADGRL4).	[14]

References

• [1] Network-based analysis of oligodendrogliomas predicts novel cancer gene candidates within the region of the 1p/19q co-deletion.Acta Neuropathol Commun. 2018 Jun 11;6(1):49. doi: 10.1186/s40478-018-0544-y.
• [2] ELTD1 facilitates glioma proliferation, migration and invasion by activating JAK/STAT3/HIF-1 signaling axis.Sci Rep. 2019 Sep 25;9(1):13904. doi: 10.1038/s41598-019-50375-x.
• [3] Augmented cardiac hypertrophy in response to pressure overload in mice lacking ELTD1.PLoS One. 2012;7(5):e35779. doi: 10.1371/journal.pone.0035779. Epub 2012 May 11.
• [4] Developmental vascular remodeling defects and postnatal kidney failure in mice lacking Gpr116 (Adgrf5) and Eltd1 (Adgrl4).PLoS One. 2017 Aug 14;12(8):e0183166. doi: 10.1371/journal.pone.0183166. eCollection 2017.
• [5] ADGRL4/ELTD1 Silencing in Endothelial Cells Induces ACLY and SLC25A1 and Alters the Cellular Metabolic Profile.Metabolites. 2019 Nov 25;9(12):287. doi: 10.3390/metabo9120287.
• [6] Microsatellite scanning of the immunogenome associates MAPK14 and ELTD1 with graft-versus-host disease in hematopoietic stem cell transplantation.Immunogenetics. 2013 Jun;65(6):417-27. doi: 10.1007/s00251-013-0691-z. Epub 2013 Mar 9.
• [7] ELTD1 Function in Hepatocellular Carcinoma is Carcinoma-Associated Fibroblast-Dependent.J Cancer. 2018 Jun 14;9(14):2415-2427. doi: 10.7150/jca.24406. eCollection 2018.
• [8] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [9] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] Transcriptomic?pathway?and?benchmark dose analysis of Bisphenol A, Bisphenol S, Bisphenol F, and 3,3',5,5'-Tetrabromobisphenol A in H9 human embryonic stem cells. Toxicol In Vitro. 2021 Apr;72:105097. doi: 10.1016/j.tiv.2021.105097. Epub 2021 Jan 18.
• [14] 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.