Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDJ5QUH)

• DOT Name: Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3)
• Synonyms: Membrane-associated guanylate kinase inverted 3; MAGI-3
• Gene Name: MAGI3
• Related Disease:
  Alopecia areata
  Autoimmune thyroid disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Glioma
  Graves disease
  Hyperthyroidism
  Hypothyroidism
  Inflammatory bowel disease
  Neoplasm
  Rheumatoid arthritis
  Type-1 diabetes
  Adenocarcinoma
  Colonic neoplasm
• UniProt ID: MAGI3_HUMAN
• PDB ID: 3SOE
• Pfam ID: PF00625 ; PF00595 ; PF00397
• Sequence:
  MSKTLKKKKHWLSKVQECAVSWAGPPGDFGAEIRGGAERGEFPYLGRLREEPGGGTCCVV
  SGKAPSPGDVLLEVNGTPVSGLTNRDTLAVIRHFREPIRLKTVKPGKVINKDLRHYLSLQ
  FQKGSIDHKLQQVIRDNLYLRTIPCTTRAPRDGEVPGVDYNFISVEQFKALEESGALLES
  GTYDGNFYGTPKPPAEPSPFQPDPVDQVLFDNEFDAESQRKRTTSVSKMERMDSSLPEEE
  EDEDKEAINGSGNAENRERHSESSDWMKTVPSYNQTNSSMDFRNYMMRDETLEPLPKNWE
  MAYTDTGMIYFIDHNTKTTTWLDPRLCKKAKAPEDCEDGELPYGWEKIEDPQYGTYYVDH
  LNQKTQFENPVEEAKRKKQLGQVEIGSSKPDMEKSHFTRDPSQLKGVLVRASLKKSTMGF
  GFTIIGGDRPDEFLQVKNVLKDGPAAQDGKIAPGDVIVDINGNCVLGHTHADVVQMFQLV
  PVNQYVNLTLCRGYPLPDDSEDPVVDIVAATPVINGQSLTKGETCMNPQDFKPGAMVLEQ
  NGKSGHTLTGDGLNGPSDASEQRVSMASSGSSQPELVTIPLIKGPKGFGFAIADSPTGQK
  VKMILDSQWCQGLQKGDIIKEIYHQNVQNLTHLQVVEVLKQFPVGADVPLLILRGGPPSP
  TKTAKMKTDKKENAGSLEAINEPIPQPMPFPPSIIRSGSPKLDPSEVYLKSKTLYEDKPP
  NTKDLDVFLRKQESGFGFRVLGGDGPDQSIYIGAIIPLGAAEKDGRLRAADELMCIDGIP
  VKGKSHKQVLDLMTTAARNGHVLLTVRRKIFYGEKQPEDDSSQAFISTQNGSPRLNRAEV
  PARPAPQEPYDVVLQRKENEGFGFVILTSKNKPPPGVIPHKIGRVIEGSPADRCGKLKVG
  DHISAVNGQSIVELSHDNIVQLIKDAGVTVTLTVIAEEEHHGPPSGTNSARQSPALQHRP
  MGQSQANHIPGDRSALEGEIGKDVSTSYRHSWSDHKHLAQPDTAVISVVGSRHNQNLGCY
  PVELERGPRGFGFSLRGGKEYNMGLFILRLAEDGPAIKDGRIHVGDQIVEINGEPTQGIT
  HTRAIELIQAGGNKVLLLLRPGTGLIPDHGDWDINNPSSSNVIYDEQSPLPPSSHFASIF
  EESHVPVIEESLRVQICEKAEELKDIVPEKKSTLNENQPEIKHQSLLQKNVSKRDPPSSH
  GHSNKKNLLKVENGVTRRGRSVSPKKPASQHSEEHLDKIPSPLKNNPKRRPRDQSLSPSK
  GENKSCQVSTRAGSGQDQCRKSRGRSASPKKQQKIEGSKAPSNAEAKLLEGKSRRIAGYT
  GSNAEQIPDGKEKSDVIRKDAKQNQLEKSRTRSPEKKIKRMVEKSLPSKMTNKTTSKEVS
  ENEKGKKVTTGETSSSNDKIGENVQLSEKRLKQEPEEKVVSNKTEDHKGKELEAADKNKE
  TGRFKPESSSPVKKTLITPGPWKVPSGNKVTGTIGMAEKRQ
• Function: Acts as a scaffolding protein at cell-cell junctions, thereby regulating various cellular and signaling processes. Cooperates with PTEN to modulate the kinase activity of AKT1. Its interaction with PTPRB and tyrosine phosphorylated proteins suggests that it may link receptor tyrosine phosphatase with its substrates at the plasma membrane. In polarized epithelial cells, involved in efficient trafficking of TGFA to the cell surface. Regulates the ability of LPAR2 to activate ERK and RhoA pathways. Regulates the JNK signaling cascade via its interaction with FZD4 and VANGL2.
• Tissue Specificity: Widely expressed.
• KEGG Pathway: Rap1 sig.ling pathway (hsa04015)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alopecia areata	DIS0XXBJ	Strong	Genetic Variation	[1]
Autoimmune thyroid disease	DISIHC6A	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Graves disease	DISU4KOQ	Strong	Biomarker	[6]
Hyperthyroidism	DISX87ZH	Strong	Genetic Variation	[7]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[7]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[10]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[2]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[11]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[16]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[17]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[20]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[23]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 3 (MAGI3).	[22]

References

• [1] Genome-wide meta-analysis in alopecia areata resolves HLA associations and reveals two new susceptibility loci.Nat Commun. 2015 Jan 22;6:5966. doi: 10.1038/ncomms6966.
• [2] Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.J Autoimmun. 2015 Jun;60:32-9. doi: 10.1016/j.jaut.2015.03.006. Epub 2015 Apr 27.
• [3] Premature polyadenylation of MAGI3 produces a dominantly-acting oncogene in human breast cancer.Elife. 2016 May 20;5:e14730. doi: 10.7554/eLife.14730.
• [4] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [5] MAGI3 Suppresses Glioma Cell Proliferation via Upregulation of PTEN Expression.Biomed Environ Sci. 2015 Jul;28(7):502-9. doi: 10.3967/bes2015.072.
• [6] The association of thyroid peroxidase antibody risk loci with susceptibility to and phenotype of Graves' disease.Clin Endocrinol (Oxf). 2015 Oct;83(4):556-62. doi: 10.1111/cen.12640. Epub 2014 Dec 22.
• [7] Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.PLoS Genet. 2014 Feb 27;10(2):e1004123. doi: 10.1371/journal.pgen.1004123. eCollection 2014 Feb.
• [8] Genetic variation and expression levels of tight junction genes identifies association between MAGI3 and inflammatory bowel disease.BMC Gastroenterol. 2017 May 25;17(1):68. doi: 10.1186/s12876-017-0620-y.
• [9] MAGI3 negatively regulates Wnt/-catenin signaling and suppresses malignant phenotypes of glioma cells.Oncotarget. 2015 Nov 3;6(34):35851-65. doi: 10.18632/oncotarget.5323.
• [10] REL, encoding a member of the NF-kappaB family of transcription factors, is a newly defined risk locus for rheumatoid arthritis.Nat Genet. 2009 Jul;41(7):820-3. doi: 10.1038/ng.395. Epub 2009 Jun 7.
• [11] MAGI-3 competes with NHERF-2 to negatively regulate LPA2 receptor signaling in colon cancer cells.Gastroenterology. 2011 Mar;140(3):924-34. doi: 10.1053/j.gastro.2010.11.054. Epub 2010 Dec 4.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] 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.
• [15] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [16] 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.
• [17] 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.
• [18] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [19] 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.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [24] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.