Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZR74BO)

• DOT Name: Insulin, isoform 2 (INS-IGF2)
• Synonyms: INS-IGF2 readthrough transcript protein
• Gene Name: INS-IGF2
• Related Disease:
  Hepatocellular carcinoma
  Alzheimer disease
  Autoimmune disease
  Beckwith-Wiedemann syndrome
  Graves disease
  Hyperglycemia
  Hypertrophic cardiomyopathy
  Insulinoma
  Lung cancer
  Lung carcinoma
  Maturity-onset diabetes of the young type 10
  Monogenic diabetes
  Multiple sclerosis
  Non-small-cell lung cancer
  Ankylosing spondylitis
  Autoimmune disease, susceptibility to, 6
  Autoimmune thyroid disease
  Coeliac disease
  Common variable immunodeficiency
  Crohn disease
  Juvenile idiopathic arthritis
  Psoriasis
  STAT3-related early-onset multisystem autoimmune disease
  Systemic lupus erythematosus
  Type-1/2 diabetes
  Ulcerative colitis
  Acute liver failure
  Non-insulin dependent diabetes
  Permanent neonatal diabetes mellitus
• UniProt ID: INSR2_HUMAN
• PDB ID: 7YQ3; 7YQ4; 7YQ5; 8GUY
• Pfam ID: PF00049
• Sequence:
  MALWMRLLPLLALLALWGPDPAAAFVNQHLCGSHLVEALYLVCGERGFFYTPKTRREAED
  LQASALSLSSSTSTWPEGLDATARAPPALVVTANIGQAGGSSSRQFRQRALGTSDSPVLF
  IHCPGAAGTAQGLEYRGRRVTTELVWEEVDSSPQPQGSESLPAQPPAQPAPQPEPQQARE
  PSPEVSCCGLWPRRPQRSQN
• Tissue Specificity: Expressed in pancreas, eye and, to a lower extent, in limb.

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[3]
Beckwith-Wiedemann syndrome	DISH15GR	Strong	Biomarker	[4]
Graves disease	DISU4KOQ	Strong	Genetic Variation	[5]
Hyperglycemia	DIS0BZB5	Strong	Genetic Variation	[6]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Genetic Variation	[7]
Insulinoma	DISIU1JS	Strong	Altered Expression	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[9]
Lung carcinoma	DISTR26C	Strong	Biomarker	[9]
Maturity-onset diabetes of the young type 10	DIS5FPQO	Strong	Genetic Variation	[6]
Monogenic diabetes	DISEB8Q0	Strong	Genetic Variation	[6]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[10]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Ankylosing spondylitis	DISRC6IR	moderate	Genetic Variation	[3]
Autoimmune disease, susceptibility to, 6	DISHNUXI	moderate	Genetic Variation	[3]
Autoimmune thyroid disease	DISIHC6A	moderate	Genetic Variation	[3]
Coeliac disease	DISIY60C	moderate	Genetic Variation	[3]
Common variable immunodeficiency	DISHE7JQ	moderate	Genetic Variation	[3]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[3]
Juvenile idiopathic arthritis	DISQZGBV	moderate	Genetic Variation	[3]
Psoriasis	DIS59VMN	moderate	Genetic Variation	[3]
STAT3-related early-onset multisystem autoimmune disease	DISAXTN7	moderate	Genetic Variation	[3]
Systemic lupus erythematosus	DISI1SZ7	moderate	Genetic Variation	[3]
Type-1/2 diabetes	DISIUHAP	moderate	Genetic Variation	[11]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[3]
Acute liver failure	DIS5EZKX	Limited	Biomarker	[12]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[13]
Permanent neonatal diabetes mellitus	DIS5AEXS	Limited	CausalMutation	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Insulin, isoform 2 (INS-IGF2).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Insulin, isoform 2 (INS-IGF2).	[16]

References

• [1] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [2] Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein.J Neurochem. 2007 May;101(3):757-70. doi: 10.1111/j.1471-4159.2006.04368.x.
• [3] 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.
• [4] Duplication of HRAS1, INS, and IGF2 is not a common event in Beckwith-Wiedemann syndrome.Ann Genet. 1988;31(4):216-20.
• [5] Evidence for a Type 1 diabetes-specific mechanism for the insulin gene-associated IDDM2 locus rather than a general influence on autoimmunity.Diabet Med. 2004 Mar;21(3):267-70. doi: 10.1111/j.1464-5491.2004.01129.x.
• [6] INS-gene mutations: from genetics and beta cell biology to clinical disease.Mol Aspects Med. 2015 Apr;42:3-18. doi: 10.1016/j.mam.2014.12.001. Epub 2014 Dec 24.
• [7] DNA sequence capture and next-generation sequencing for the molecular diagnosis of genetic cardiomyopathies.J Mol Diagn. 2014 Jan;16(1):32-44. doi: 10.1016/j.jmoldx.2013.07.008. Epub 2013 Oct 31.
• [8] Upregulation of INS-IGF2 read-through expression and identification of a novel INS-IGF2 splice variant in insulinomas.Oncol Rep. 2016 Nov;36(5):2653-2662. doi: 10.3892/or.2016.5132. Epub 2016 Sep 23.
• [9] lncINS-IGF2 Promotes Cell Proliferation and Migration by Promoting G1/S Transition in Lung Cancer.Technol Cancer Res Treat. 2019 Jan 1;18:1533033818823029. doi: 10.1177/1533033818823029.
• [10] Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci.Ann Neurol. 2011 Dec;70(6):897-912. doi: 10.1002/ana.22609.
• [11] Parental imprinting effect at the INS-IGF2 diabetes susceptibility locus.Diabetologia. 1995 Jun;38(6):715-9. doi: 10.1007/BF00401845.
• [12] Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure.Biochim Biophys Acta. 2007 Jan;1772(1):60-5. doi: 10.1016/j.bbadis.2006.10.001. Epub 2006 Oct 4.
• [13] First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.Diabetes Care. 2018 Nov;41(11):2396-2403. doi: 10.2337/dc18-1032. Epub 2018 Sep 25.
• [14] Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus.J Biol Chem. 2011 Aug 12;286(32):28414-24. doi: 10.1074/jbc.M110.215822. Epub 2011 May 18.
• [15] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [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.