Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTRCTKV9)

• DOT Name: Angiomotin-like protein 2 (AMOTL2)
• Synonyms: Leman coiled-coil protein; LCCP
• Gene Name: AMOTL2
• Related Disease:
  Adult glioblastoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Liver cancer
  Metastatic malignant neoplasm
• UniProt ID: AMOL2_HUMAN
• Pfam ID: PF12240
• Sequence:
  MRTLEDSSGTVLHRLIQEQLRYGNLTETRTLLAIQQQALRGGAGTGGTGSPQASLEILAP
  EDSQVLQQATRQEPQGQEHQGGENHLAENTLYRLCPQPSKGEELPTYEEAKAHSQYYAAQ
  QAGTRPHAGDRDPRGAPGGSRRQDEALRELRHGHVRSLSERLLQLSLERNGARAPSHMSS
  SHSFPQLARNQQGPPLRGPPAEGPESRGPPPQYPHVVLAHETTTAVTDPRYRARGSPHFQ
  HAEVRILQAQVPPVFLQQQQQYQYLQQSQEHPPPPHPAALGHGPLSSLSPPAVEGPVSAQ
  ASSATSGSAHLAQMEAVLRENARLQRDNERLQRELESSAEKAGRIEKLESEIQRLSEAHE
  SLTRASSKREALEKTMRNKMDSEMRRLQDFNRDLRERLESANRRLASKTQEAQAGSQDMV
  AKLLAQSYEQQQEQEKLEREMALLRGAIEDQRRRAELLEQALGNAQGRAARAEEELRKKQ
  AYVEKVERLQQALGQLQAACEKREQLELRLRTRLEQELKALRAQQRQAGAPGGSSGSGGS
  PELSALRLSEQLREKEEQILALEADMTKWEQKYLEERAMRQFAMDAAATAAAQRDTTLIR
  HSPQPSPSSSFNEGLLTGGHRHQEMESRLKVLHAQILEKDAVIKVLQQRSRRDPGKAIQG
  SLRPAKSVPSVFAAAAAGTQGWQGLSSSERQTADAPARLTTDRAPTEEPVVTAPPAAHAK
  HGSRDGSTQTEGPPDSTSTCLPPEPDSLLGCSSSQRAASLDSVATSRVQDLSDMVEILI
• Function: Regulates the translocation of phosphorylated SRC to peripheral cell-matrix adhesion sites. Required for proper architecture of actin filaments. Inhibits the Wnt/beta-catenin signaling pathway, probably by recruiting CTNNB1 to recycling endosomes and hence preventing its translocation to the nucleus. Participates in angiogenesis. May play a role in the polarity, proliferation and migration of endothelial cells. Selectively promotes FGF-induced MAPK activation through SRC.
• KEGG Pathway: Tight junction (hsa04530)
• Reactome Pathway: Signaling by Hippo (R-HSA-2028269)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Liver cancer	DISDE4BI	Strong	Altered Expression	[4]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[3]

15 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 Angiomotin-like protein 2 (AMOTL2).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Angiomotin-like protein 2 (AMOTL2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Angiomotin-like protein 2 (AMOTL2).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Angiomotin-like protein 2 (AMOTL2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Angiomotin-like protein 2 (AMOTL2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Angiomotin-like protein 2 (AMOTL2).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Angiomotin-like protein 2 (AMOTL2).	[11]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Angiomotin-like protein 2 (AMOTL2).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Angiomotin-like protein 2 (AMOTL2).	[13]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Angiomotin-like protein 2 (AMOTL2).	[11]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of Angiomotin-like protein 2 (AMOTL2).	[15]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Angiomotin-like protein 2 (AMOTL2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Angiomotin-like protein 2 (AMOTL2).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Angiomotin-like protein 2 (AMOTL2).	[20]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Angiomotin-like protein 2 (AMOTL2).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Angiomotin-like protein 2 (AMOTL2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Angiomotin-like protein 2 (AMOTL2).	[16]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Angiomotin-like protein 2 (AMOTL2).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Angiomotin-like protein 2 (AMOTL2).	[19]

References

• [1] IQGAP1, AmotL2, and FKBP51 Scaffoldins in the Glioblastoma Microenvironment.J Histochem Cytochem. 2019 Jul;67(7):481-494. doi: 10.1369/0022155419833334. Epub 2019 Feb 22.
• [2] AmotL2 disrupts apical-basal cell polarity and promotes tumour invasion.Nat Commun. 2014 Aug 1;5:4557. doi: 10.1038/ncomms5557.
• [3] Commitment of Scaffold Proteins in the Onco-Biology of Human Colorectal Cancer and Liver Metastases after Oxaliplatin-Based Chemotherapy.Int J Mol Sci. 2017 Apr 22;18(4):891. doi: 10.3390/ijms18040891.
• [4] Angiomotin-like 2 interacts with and negatively regulates AKT.Oncogene. 2017 Aug 10;36(32):4662-4669. doi: 10.1038/onc.2017.101. Epub 2017 Apr 3.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] 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.
• [11] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [16] 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.
• [17] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [18] 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.
• [19] 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.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] Probiotic Bacillus subtilis CW14 reduces disruption of the epithelial barrier and toxicity of ochratoxin A to Caco-2?cells. Food Chem Toxicol. 2019 Apr;126:25-33. doi: 10.1016/j.fct.2019.02.009. Epub 2019 Feb 11.