Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8GIIS5)

• DOT Name: Abl interactor 2 (ABI2)
• Synonyms: Abelson interactor 2; Abi-2; Abl-binding protein 3; AblBP3; Arg-binding protein 1; ArgBP1
• Gene Name: ABI2
• Related Disease:
  Amyloidosis
  Cardiovascular disease
  Cholangiocarcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Inflammatory bowel disease
  Leiomyoma
  Lung cancer
  Lung carcinoma
  Ocular melanoma
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Melanoma
  Arteriosclerosis
• UniProt ID: ABI2_HUMAN
• PDB ID: 2ED0; 3P8C; 4N78; 7USC; 7USD; 7USE
• Pfam ID: PF07815 ; PF00018
• Sequence:
  MAELQMLLEEEIPGGRRALFDSYTNLERVADYCENNYIQSADKQRALEETKAYTTQSLAS
  VAYLINTLANNVLQMLDIQASQLRRMESSINHISQTVDIHKEKVARREIGILTTNKNTSR
  THKIIAPANLERPVRYIRKPIDYTILDDIGHGVKWLLRFKVSTQNMKMGGLPRTTPPTQK
  PPSPPMSGKGTLGRHSPYRTLEPVRPPVVPNDYVPSPTRNMAPSQQSPVRTASVNQRNRT
  YSSSGSSGGSHPSSRSSSRENSGSGSVGVPIAVPTPSPPSVFPAPAGSAGTPPLPATSAS
  APAPLVPATVPSSTAPNAAAGGAPNLADGFTSPTPPVVSSTPPTGHPVQFYSMNRPASRH
  TPPTIGGSLPYRRPPSITSQTSLQNQMNGGPFYSQNPVSDTPPPPPPVEEPVFDESPPPP
  PPPEDYEEEEAAVVEYSDPYAEEDPPWAPRSYLEKVVAIYDYTKDKEDELSFQEGAIIYV
  IKKNDDGWYEGVMNGVTGLFPGNYVESIMHYSE
• Function: Regulator of actin cytoskeleton dynamics underlying cell motility and adhesion. Functions as a component of the WAVE complex, which activates actin nucleating machinery Arp2/3 to drive lamellipodia formation. Acts as a regulator and substrate of nonreceptor tyrosine kinases ABL1 and ABL2 involved in processes linked to cell growth and differentiation. Positively regulates ABL1-mediated phosphorylation of ENAH, which is required for proper polymerization of nucleated actin filaments at the leading edge. Contributes to the regulation of actin assembly at the tips of neuron projections. In particular, controls dendritic spine morphogenesis and may promote dendritic spine specification toward large mushroom-type spines known as repositories of memory in the brain. In hippocampal neurons, may mediate actin-dependent BDNF-NTRK2 early endocytic trafficking that triggers dendrite outgrowth. Participates in ocular lens morphogenesis, likely by regulating lamellipodia-driven adherens junction formation at the epithelial cell-secondary lens fiber interface. Also required for nascent adherens junction assembly in epithelial cells.
• Tissue Specificity: Widely expressed. Abundant in testes, ovary, thymus, and colon, with lower but detectable levels in prostate, peripheral blood leukocytes, and spleen.
• KEGG Pathway: Regulation of actin cytoskeleton (hsa04810)
• Reactome Pathway:
  VEGFA-VEGFR2 Pathway (R-HSA-4420097)
  RHO GTPases Activate WASPs and WAVEs (R-HSA-5663213)
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC2 GTPase cycle (R-HSA-9013404)
  RAC3 GTPase cycle (R-HSA-9013423)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[1]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[2]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[5]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[4]
Leiomyoma	DISLDDFN	Strong	Biomarker	[6]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[7]
Lung carcinoma	DISTR26C	Strong	Genetic Variation	[7]
Ocular melanoma	DISOHHFC	Strong	Biomarker	[8]
Atherosclerosis	DISMN9J3	moderate	Altered Expression	[9]
Breast cancer	DIS7DPX1	moderate	Genetic Variation	[10]
Breast carcinoma	DIS2UE88	moderate	Genetic Variation	[10]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[10]
Arteriosclerosis	DISK5QGC	Limited	Biomarker	[11]

11 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 Abl interactor 2 (ABI2).	[12]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Abl interactor 2 (ABI2).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Abl interactor 2 (ABI2).	[14]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Abl interactor 2 (ABI2).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Abl interactor 2 (ABI2).	[16]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Abl interactor 2 (ABI2).	[18]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Abl interactor 2 (ABI2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Abl interactor 2 (ABI2).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Abl interactor 2 (ABI2).	[21]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of Abl interactor 2 (ABI2).	[23]
Manganese	DMKT129	Investigative	Manganese increases the expression of Abl interactor 2 (ABI2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Abl interactor 2 (ABI2).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Abl interactor 2 (ABI2).	[22]

References

• [1] Antiamyloidogenic Activity of A42-Binding Peptoid in Modulating Amyloid Oligomerization.Small. 2017 Jan;13(1). doi: 10.1002/smll.201602857. Epub 2016 Oct 7.
• [2] AIP1-mediated stress signaling in atherosclerosis and arteriosclerosis.Curr Atheroscler Rep. 2015 May;17(5):503. doi: 10.1007/s11883-015-0503-z.
• [3] Outcome and Genetic Factors in IgG4-Associated Autoimmune Pancreatitis and Cholangitis: A Single Center Experience.Gastroenterol Res Pract. 2017;2017:6126707. doi: 10.1155/2017/6126707. Epub 2017 Mar 2.
• [4] Suppression of inflammation and tissue damage by a hookworm recombinant protein in experimental colitis.Clin Transl Immunology. 2017 Oct 6;6(10):e157. doi: 10.1038/cti.2017.42. eCollection 2017 Oct.
• [5] Low expression level of ASK1-interacting protein-1 correlated with tumor angiogenesis and poor survival in patients with esophageal squamous cell cancer.Onco Targets Ther. 2018 Nov 1;11:7699-7707. doi: 10.2147/OTT.S178131. eCollection 2018.
• [6] The expression of Abl interactor 2 in leiomyoma and myometrium and regulation by GnRH analogue and transforming growth factor-beta.Hum Reprod. 2006 Jun;21(6):1380-6. doi: 10.1093/humrep/del011. Epub 2006 Feb 17.
• [7] A common genetic variant (97906C>A) of DAB2IP/AIP1 is associated with an increased risk and early onset of lung cancer in Chinese males.PLoS One. 2011;6(10):e26944. doi: 10.1371/journal.pone.0026944. Epub 2011 Oct 26.
• [8] Ca2+ binding to EF hands 1 and 3 is essential for the interaction of apoptosis-linked gene-2 with Alix/AIP1 in ocular melanoma.Biochemistry. 2004 Sep 7;43(35):11175-86. doi: 10.1021/bi048848d.
• [9] Endothelial AIP1 Regulates Vascular Remodeling by Suppressing NADPH Oxidase-2.Front Physiol. 2018 Apr 20;9:396. doi: 10.3389/fphys.2018.00396. eCollection 2018.
• [10] AIP1 Expression in Tumor Niche Suppresses Tumor Progression and Metastasis.Cancer Res. 2015 Sep 1;75(17):3492-504. doi: 10.1158/0008-5472.CAN-15-0088. Epub 2015 Jul 2.
• [11] Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction.Arterioscler Thromb Vasc Biol. 2020 Jan;40(1):112-127. doi: 10.1161/ATVBAHA.119.312976. Epub 2019 Oct 17.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [14] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] Chronic occupational exposure to arsenic induces carcinogenic gene signaling networks and neoplastic transformation in human lung epithelial cells. Toxicol Appl Pharmacol. 2012 Jun 1;261(2):204-16.
• [19] Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17-25. doi: 10.1159/000287353. Epub 2010 Feb 24.
• [20] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [21] 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.
• [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] Effects of lithium and valproic acid on gene expression and phenotypic markers in an NT2 neurosphere model of neural development. PLoS One. 2013;8(3):e58822.
• [24] Gene expression profiling of human primary astrocytes exposed to manganese chloride indicates selective effects on several functions of the cells. Neurotoxicology. 2007 May;28(3):478-89.