Details of Drug Off-Target (DOT)

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

• DOT Name: Integral membrane protein 2B (ITM2B)
• Synonyms: Immature BRI2; imBRI2; Protein E25B; Transmembrane protein BRI; Bri
• Gene Name: ITM2B
• Related Disease:
  Non-insulin dependent diabetes
  ABri amyloidosis
  Adult lymphoma
  Adult respiratory distress syndrome
  Amyloidosis
  Attention deficit hyperactivity disorder
  B-cell neoplasm
  Breast cancer
  Breast carcinoma
  Cerebellar ataxia
  Familial Alzheimer disease
  Frontotemporal dementia
  Gastric cancer
  Hereditary amyloidosis
  High blood pressure
  Inherited retinal dystrophy
  Irritable bowel syndrome
  Lymphoma
  Neoplasm
  Pediatric lymphoma
  Pick disease
  Pneumonitis
  Prostate neoplasm
  Retinopathy
  Stomach cancer
  T-cell lymphoma
  Age-related macular degeneration
  ADan amyloidosis
  Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies
  Chondrosarcoma
  Congenital alveolar dysplasia
  Neuroblastoma
  Stroke
• UniProt ID: ITM2B_HUMAN
• Pfam ID: PF04089
• Sequence:
  MVKVTFNSALAQKEAKKDEPKSGEEALIIPPDAVAVDCKDPDDVVPVGQRRAWCWCMCFG
  LAFMLAGVILGGAYLYKYFALQPDDVYYCGIKYIKDDVILNEPSADAPAALYQTIEENIK
  IFEEEEVEFISVPVPEFADSDPANIVHDFNKKLTAYLDLNLDKCYVIPLNTSIVMPPRNL
  LELLINIKAGTYLPQSYLIHEHMVITDRIENIDHLGFFIYRLCHDKETYKLQRRETIKGI
  QKREASNCFAIRHFENKFAVETLICS
• Function: Plays a regulatory role in the processing of the amyloid-beta A4 precursor protein (APP) and acts as an inhibitor of the amyloid-beta peptide aggregation and fibrils deposition. Plays a role in the induction of neurite outgrowth. Functions as a protease inhibitor by blocking access of secretases to APP cleavage sites.; Mature BRI2 (mBRI2) functions as a modulator of the amyloid-beta A4 precursor protein (APP) processing leading to a strong reduction in the secretion of secretase-processed amyloid-beta protein 40 and amyloid-beta protein 42.; Bri23 peptide prevents aggregation of APP amyloid-beta protein 42 into toxic oligomers.
• Tissue Specificity: Ubiquitous. Expressed in brain.
• Reactome Pathway: Amyloid fiber formation (R-HSA-977225)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[1]
ABri amyloidosis	DIS3Y5TL	Strong	Autosomal dominant	[2]
Adult lymphoma	DISK8IZR	Strong	Biomarker	[3]
Adult respiratory distress syndrome	DISIJV47	Strong	Genetic Variation	[4]
Amyloidosis	DISHTAI2	Strong	Biomarker	[5]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[6]
B-cell neoplasm	DISVY326	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[7]
Cerebellar ataxia	DIS9IRAV	Strong	Genetic Variation	[8]
Familial Alzheimer disease	DISE75U4	Strong	Biomarker	[9]
Frontotemporal dementia	DISKYHXL	Strong	Genetic Variation	[10]
Gastric cancer	DISXGOUK	Strong	Biomarker	[11]
Hereditary amyloidosis	DIS1GS6H	Strong	Genetic Variation	[12]
High blood pressure	DISY2OHH	Strong	Biomarker	[13]
Inherited retinal dystrophy	DISGGL77	Strong	Biomarker	[14]
Irritable bowel syndrome	DIS27206	Strong	Biomarker	[15]
Lymphoma	DISN6V4S	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Pediatric lymphoma	DIS51BK2	Strong	Biomarker	[3]
Pick disease	DISP6X50	Strong	Genetic Variation	[10]
Pneumonitis	DIS88E0K	Strong	Biomarker	[16]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[17]
Retinopathy	DISB4B0F	Strong	Genetic Variation	[18]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[3]
Age-related macular degeneration	DIS0XS2C	moderate	Altered Expression	[19]
ADan amyloidosis	DISXF54F	Supportive	Autosomal dominant	[20]
Retinal dystrophy with inner retinal dysfunction and ganglion cell anomalies	DISCB00J	Supportive	Autosomal dominant	[18]
Chondrosarcoma	DIS4I7JB	Limited	Genetic Variation	[4]
Congenital alveolar dysplasia	DIS1IYUN	Limited	Genetic Variation	[4]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[21]
Stroke	DISX6UHX	Limited	Biomarker	[20]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Integral membrane protein 2B (ITM2B) affects the response to substance of Paclitaxel.	[39]

16 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 Integral membrane protein 2B (ITM2B).	[22]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Integral membrane protein 2B (ITM2B).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Integral membrane protein 2B (ITM2B).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integral membrane protein 2B (ITM2B).	[25]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Integral membrane protein 2B (ITM2B).	[26]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Integral membrane protein 2B (ITM2B).	[27]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integral membrane protein 2B (ITM2B).	[28]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Integral membrane protein 2B (ITM2B).	[30]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Integral membrane protein 2B (ITM2B).	[31]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Integral membrane protein 2B (ITM2B).	[32]
Isoflavone	DM7U58J	Phase 4	Isoflavone increases the expression of Integral membrane protein 2B (ITM2B).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Integral membrane protein 2B (ITM2B).	[34]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Integral membrane protein 2B (ITM2B).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Integral membrane protein 2B (ITM2B).	[36]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Integral membrane protein 2B (ITM2B).	[37]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Integral membrane protein 2B (ITM2B).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the ubiquitination of Integral membrane protein 2B (ITM2B).	[29]

References

• [1] Using different anthropometric indices to assess prediction ability of type 2 diabetes in elderly population: a 5year prospective study.BMC Geriatr. 2018 Sep 17;18(1):218. doi: 10.1186/s12877-018-0912-2.
• [2] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [3] The ITM2B (BRI2) gene is a target of BCL6 repression: Implications for lymphomas and neurodegenerative diseases.Biochim Biophys Acta. 2015 May;1852(5):742-8. doi: 10.1016/j.bbadis.2014.12.018. Epub 2014 Dec 31.
• [4] BRICHOS domain associated with lung fibrosis, dementia and cancer--a chaperone that prevents amyloid fibril formation?.FEBS J. 2011 Oct;278(20):3893-904. doi: 10.1111/j.1742-4658.2011.08209.x. Epub 2011 Jul 5.
• [5] Memory deficits due to familial British dementia BRI2 mutation are caused by loss of BRI2 function rather than amyloidosis.J Neurosci. 2010 Nov 3;30(44):14915-24. doi: 10.1523/JNEUROSCI.3917-10.2010.
• [6] The Behavior Rating Inventory of Executive Function (BRIEF) to Identify Pediatric Acute Lymphoblastic Leukemia (ALL) Survivors At Risk for Neurocognitive Impairment.J Pediatr Hematol Oncol. 2017 Apr;39(3):174-178. doi: 10.1097/MPH.0000000000000761.
• [7] Magnetic resonance imaging response monitoring of breast cancer during neoadjuvant chemotherapy: relevance of breast cancer subtype.J Clin Oncol. 2011 Feb 20;29(6):660-6. doi: 10.1200/JCO.2010.31.1258. Epub 2011 Jan 10.
• [8] Familial Danish dementia: co-existence of Danish and Alzheimer amyloid subunits (ADan AND A{beta}) in the absence of compact plaques.J Biol Chem. 2005 Nov 4;280(44):36883-94. doi: 10.1074/jbc.M504038200. Epub 2005 Aug 9.
• [9] Deletion of the -secretase subunits Aph1B/C impairs memory and worsens the deficits of knock-in mice modeling the Alzheimer-like familial Danish dementia.Oncotarget. 2016 Mar 15;7(11):11923-44. doi: 10.18632/oncotarget.7389.
• [10] Early onset autosomal dominant dementia with ataxia, extrapyramidal features, and epilepsy.Neurology. 2002 Mar 26;58(6):922-8. doi: 10.1212/wnl.58.6.922.
• [11] BRICHOS: a conserved domain in proteins associated with dementia, respiratory distress and cancer.Trends Biochem Sci. 2002 Jul;27(7):329-32. doi: 10.1016/s0968-0004(02)02134-5.
• [12] Genetics and molecular pathogenesis of sporadic and hereditary cerebral amyloid angiopathies.Acta Neuropathol. 2009 Jul;118(1):115-30. doi: 10.1007/s00401-009-0501-8. Epub 2009 Feb 19.
• [13] A custom rat and baboon hypertension gene array to compare experimental models.Exp Biol Med (Maywood). 2012 Jan;237(1):99-110. doi: 10.1258/ebm.2011.011188. Epub 2012 Jan 6.
• [14] Generation of human induced pluripotent stem cell lines from a patient with ITM2B-related retinal dystrophy and a non mutated brother. Stem Cell Res. 2019 Dec;41:101625. doi: 10.1016/j.scr.2019.101625. Epub 2019 Nov 5.
• [15] What impact do Rome IV criteria have on patients with IBS in China?.Scand J Gastroenterol. 2019 Dec;54(12):1433-1440. doi: 10.1080/00365521.2019.1698650. Epub 2019 Dec 12.
• [16] Autoimmune antibodies correlate with immune checkpoint therapy-induced toxicities.Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22246-22251. doi: 10.1073/pnas.1908079116. Epub 2019 Oct 14.
• [17] Transcriptome profiling of a TGF-beta-induced epithelial-to-mesenchymal transition reveals extracellular clusterin as a target for therapeutic antibodies.Oncogene. 2010 Feb 11;29(6):831-44. doi: 10.1038/onc.2009.399. Epub 2009 Nov 23.
• [18] The familial dementia gene revisited: a missense mutation revealed by whole-exome sequencing identifies ITM2B as a candidate gene underlying a novel autosomal dominant retinal dystrophy in a large family. Hum Mol Genet. 2014 Jan 15;23(2):491-501. doi: 10.1093/hmg/ddt439. Epub 2013 Sep 10.
• [19] Amyloid peptides overexpression in retinal pigment epithelial cells via AAV-mediated gene transfer mimics AMD-like pathology in mice.Sci Rep. 2017 Jun 12;7(1):3222. doi: 10.1038/s41598-017-03397-2.
• [20] A decamer duplication in the 3' region of the BRI gene originates an amyloid peptide that is associated with dementia in a Danish kindred. Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4920-5. doi: 10.1073/pnas.080076097.
• [21] BRI2 ectodomain affects A42 fibrillation and tau truncation in human neuroblastoma cells.Cell Mol Life Sci. 2015 Apr;72(8):1599-611. doi: 10.1007/s00018-014-1769-y. Epub 2014 Oct 22.
• [22] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [23] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [24] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [25] 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.
• [26] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [27] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [28] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [29] Quantitative Assessment of Arsenite-Induced Perturbation of Ubiquitinated Proteome. Chem Res Toxicol. 2022 Sep 19;35(9):1589-1597. doi: 10.1021/acs.chemrestox.2c00197. Epub 2022 Aug 22.
• [30] 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.
• [31] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [32] 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.
• [33] Soy isoflavones exert differential effects on androgen responsive genes in LNCaP human prostate cancer cells. J Nutr. 2007 Apr;137(4):964-72.
• [34] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [35] 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.
• [36] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [37] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [38] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.
• [39] 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.