Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCVQD60)

• DOT Name: Microtubule-associated protein RP/EB family member 1 (MAPRE1)
• Synonyms: APC-binding protein EB1; End-binding protein 1; EB1
• Gene Name: MAPRE1
• Related Disease:
  Nephropathy
  Acute lymphocytic leukaemia
  B-cell acute lymphoblastic leukaemia
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Familial adenomatous polyposis
  Gastric cancer
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Myocardial ischemia
  Non-small-cell lung cancer
  Polycystic ovarian syndrome
  Stomach cancer
  Ulcerative colitis
  Squamous cell carcinoma
  Advanced cancer
  Classic lissencephaly
  Neoplasm
• UniProt ID: MARE1_HUMAN
• PDB ID: 1PA7; 1TXQ; 1UEG; 1VKA; 1WU9; 1YIB; 1YIG; 2HKQ; 2HL3; 2HL5; 2QJZ; 2R8U; 3GJO; 3MTU; 3MUD; 3TQ7; 4XA1; 4XA3; 4XA6; 5JV3; 5JVM; 5JVP; 5JVR; 5JVS; 5JVU; 5JX1; 5WLQ; 6PF2; 6PFP; 6YF5; 6YSH
• Pfam ID: PF00307 ; PF03271
• Sequence:
  MAVNVYSTSVTSDNLSRHDMLAWINESLQLNLTKIEQLCSGAAYCQFMDMLFPGSIALKK
  VKFQAKLEHEYIQNFKILQAGFKRMGVDKIIPVDKLVKGKFQDNFEFVQWFKKFFDANYD
  GKDYDPVAARQGQETAVAPSLVAPALNKPKKPLTSSSAAPQRPISTQRTAAAPKAGPGVV
  RKNPGVGNGDDEAAELMQQVNVLKLTVEDLEKERDFYFGKLRNIELICQENEGENDPVLQ
  RIVDILYATDEGFVIPDEGGPQEEQEEY
• Function: Plus-end tracking protein (+TIP) that binds to the plus-end of microtubules and regulates the dynamics of the microtubule cytoskeleton. Promotes cytoplasmic microtubule nucleation and elongation. Involved in mitotic spindle positioning by stabilizing microtubules and promoting dynamic connection between astral microtubules and the cortex during mitotic chromosome segregation. Also acts as a regulator of minus-end microtubule organization: interacts with the complex formed by AKAP9 and PDE4DIP, leading to recruit CAMSAP2 to the Golgi apparatus, thereby tethering non-centrosomal minus-end microtubules to the Golgi, an important step for polarized cell movement. Promotes elongation of CAMSAP2-decorated microtubule stretches on the minus-end of microtubules. Acts as a regulator of autophagosome transport via interaction with CAMSAP2. Functions downstream of Rho GTPases and DIAPH1 in stable microtubule formation. May play a role in cell migration.
• Tissue Specificity: Ubiquitously expressed.
• Reactome Pathway:
  Separation of Sister Chromatids (R-HSA-2467813)
  Resolution of Sister Chromatid Cohesion (R-HSA-2500257)
  Regulation of PLK1 Activity at G2/M Transition (R-HSA-2565942)
  Loss of Nlp from mitotic centrosomes (R-HSA-380259)
  Recruitment of mitotic centrosome proteins and complexes (R-HSA-380270)
  Loss of proteins required for interphase microtubule organization from the centrosome (R-HSA-380284)
  Recruitment of NuMA to mitotic centrosomes (R-HSA-380320)
  Anchoring of the basal body to the plasma membrane (R-HSA-5620912)
  RHO GTPases Activate Formins (R-HSA-5663220)
  Mitotic Prometaphase (R-HSA-68877)
  The role of GTSE1 in G2/M progression after G2 checkpoint (R-HSA-8852276)
  AURKA Activation by TPX2 (R-HSA-8854518)
  EML4 and NUDC in mitotic spindle formation (R-HSA-9648025)
  Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal (R-HSA-141444)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Genetic Variation	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[2]
B-cell acute lymphoblastic leukaemia	DISKLOKC	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[4]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[9]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[11]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[13]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[3]
Classic lissencephaly	DISR8S3S	Limited	Biomarker	[14]
Neoplasm	DISZKGEW	Limited	Altered Expression	[3]

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 Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[16]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[20]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[21]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[23]
Mitomycin	DMH0ZJE	Approved	Mitomycin increases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[24]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[23]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[29]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[30]

2 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the localization of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[22]
Rigosertib	DMOSTXF	Phase 3	Rigosertib affects the localization of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[25]

4 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 decreases the methylation of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[26]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[28]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Microtubule-associated protein RP/EB family member 1 (MAPRE1).	[27]

References

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• [2] MLL is fused to EB1 (MAPRE1), which encodes a microtubule-associated protein, in a patient with acute lymphoblastic leukemia.Genes Chromosomes Cancer. 2005 Jun;43(2):206-10. doi: 10.1002/gcc.20174.
• [3] Combinatorial expression of microtubule-associated EB1 and ATIP3 biomarkers improves breast cancer prognosis.Breast Cancer Res Treat. 2019 Feb;173(3):573-583. doi: 10.1007/s10549-018-5026-1. Epub 2018 Oct 27.
• [4] End-binding protein 1 stimulates paclitaxel sensitivity in breast cancer by promoting its actions toward microtubule assembly and stability.Protein Cell. 2014 Jun;5(6):469-79. doi: 10.1007/s13238-014-0053-0. Epub 2014 Apr 19.
• [5] End-binding protein 1 (EB1) up-regulation is an early event in colorectal carcinogenesis.FEBS Lett. 2014 Mar 3;588(5):829-35. doi: 10.1016/j.febslet.2014.01.046. Epub 2014 Feb 1.
• [6] Epigenetic regulation of microRNA-10b and targeting of oncogenic MAPRE1 in gastric cancer.Epigenetics. 2011 Jun;6(6):740-51. doi: 10.4161/epi.6.6.15874. Epub 2011 Jun 1.
• [7] Identifying the optimal gene and gene set in hepatocellular carcinoma based on differential expression and differential co-expression algorithm.Oncol Rep. 2017 Feb;37(2):1066-1074. doi: 10.3892/or.2016.5333. Epub 2016 Dec 23.
• [8] Knockdown of end-binding protein 1 induces apoptosis in radioresistant A549 lung cancer cells via p38 kinase-dependent COX-2 upregulation.Oncol Rep. 2018 Apr;39(4):1565-1572. doi: 10.3892/or.2018.6278. Epub 2018 Feb 22.
• [9] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [10] Depletion of end-binding protein 1 (EB1) promotes apoptosis of human non-small-cell lung cancer cells via reactive oxygen species and Bax-mediated mitochondrial dysfunction.Cancer Lett. 2013 Oct 1;339(1):15-24. doi: 10.1016/j.canlet.2013.07.027. Epub 2013 Jul 27.
• [11] Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria.PLoS Genet. 2018 Dec 19;14(12):e1007813. doi: 10.1371/journal.pgen.1007813. eCollection 2018 Dec.
• [12] EB1 protein alteration characterizes sporadic but not ulcerative colitis associated colorectal cancer.Oncotarget. 2017 Jul 4;8(33):54939-54950. doi: 10.18632/oncotarget.18978. eCollection 2017 Aug 15.
• [13] End Binding 1 (EB1) overexpression in oral lesions and cancer: A biomarker of tumor progression and poor prognosis.Clin Chim Acta. 2016 Aug 1;459:45-52. doi: 10.1016/j.cca.2016.05.012. Epub 2016 May 18.
• [14] Lissencephaly-1 is a context-dependent regulator of the human dynein complex.Elife. 2017 Apr 13;6:e21768. doi: 10.7554/eLife.21768.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] 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.
• [20] 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.
• [21] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [22] Olesoxime prevents microtubule-targeting drug neurotoxicity: selective preservation of EB comets in differentiated neuronal cells. Biochem Pharmacol. 2010 Sep 15;80(6):884-94. doi: 10.1016/j.bcp.2010.04.018. Epub 2010 Apr 22.
• [23] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [24] Genomic and proteomic profiling of responses to toxic metals in human lung cells. Environ Health Perspect. 2003 May;111(6):825-35.
• [25] Centmitor-1, a novel acridinyl-acetohydrazide, possesses similar molecular interaction field and antimitotic cellular phenotype as rigosertib, on 01910.Na. Mol Cancer Ther. 2014 May;13(5):1054-66. doi: 10.1158/1535-7163.MCT-13-0685. Epub 2014 Apr 18.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Ochratoxin a lowers mRNA levels of genes encoding for key proteins of liver cell metabolism. Cancer Genomics Proteomics. 2008 Nov-Dec;5(6):319-32.