Details of Drug Off-Target (DOT)

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

• DOT Name: Integrin beta-1-binding protein 1 (ITGB1BP1)
• Synonyms: Integrin cytoplasmic domain-associated protein 1; ICAP-1
• Gene Name: ITGB1BP1
• Related Disease:
  Bone development disease
  Cerebral cavernous malformation
  Non-insulin dependent diabetes
  Plasma cell myeloma
  Small lymphocytic lymphoma
• UniProt ID: ITBP1_HUMAN
• PDB ID: 4DX8; 4DX9; 4JIF
• Pfam ID: PF10480
• Sequence:
  MFRKGKKRHSSSSSQSSEISTKSKSVDSSLGGLSRSSTVASLDTDSTKSSGQSNNNSDTC
  AEFRIKYVGAIEKLKLSEGKGLEGPLDLINYIDVAQQDGKLPFVPPEEEFIMGVSKYGIK
  VSTSDQYDVLHRHALYLIIRMVCYDDGLGAGKSLLALKTTDASNEEYSLWVYQCNSLEQA
  QAICKVLSTAFDSVLTSEKP
• Function: Key regulator of the integrin-mediated cell-matrix interaction signaling by binding to the ITGB1 cytoplasmic tail and preventing the activation of integrin alpha-5/beta-1 (heterodimer of ITGA5 and ITGB1) by talin or FERMT1. Plays a role in cell proliferation, differentiation, spreading, adhesion and migration in the context of mineralization and bone development and angiogenesis. Stimulates cellular proliferation in a fibronectin-dependent manner. Involved in the regulation of beta-1 integrin-containing focal adhesion (FA) site dynamics by controlling its assembly rate during cell adhesion; inhibits beta-1 integrin clustering within FA by directly competing with talin TLN1, and hence stimulates osteoblast spreading and migration in a fibronectin- and/or collagen-dependent manner. Acts as a guanine nucleotide dissociation inhibitor (GDI) by regulating Rho family GTPases during integrin-mediated cell matrix adhesion; reduces the level of active GTP-bound form of both CDC42 and RAC1 GTPases upon cell adhesion to fibronectin. Stimulates the release of active CDC42 from the membranes to maintain it in an inactive cytoplasmic pool. Participates in the translocation of the Rho-associated protein kinase ROCK1 to membrane ruffles at cell leading edges of the cell membrane, leading to an increase of myoblast cell migration on laminin. Plays a role in bone mineralization at a late stage of osteoblast differentiation; modulates the dynamic formation of focal adhesions into fibrillar adhesions, which are adhesive structures responsible for fibronectin deposition and fibrillogenesis. Plays a role in blood vessel development; acts as a negative regulator of angiogenesis by attenuating endothelial cell proliferation and migration, lumen formation and sprouting angiogenesis by promoting AKT phosphorylation and inhibiting ERK1/2 phosphorylation through activation of the Notch signaling pathway. Promotes transcriptional activity of the MYC promoter.
• Tissue Specificity: Expressed in endothelial cells and fibroblasts (at protein level). Ubiquitously expressed. Expressed in intestine, colon, testis, ovary, thymus, spleen and prostate.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone development disease	DISVKAZS	Strong	Biomarker	[1]
Cerebral cavernous malformation	DISLKNYA	Strong	Biomarker	[2]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Altered Expression	[3]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[4]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[4]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Integrin beta-1-binding protein 1 (ITGB1BP1) affects the response to substance of Paclitaxel.	[18]
Vinblastine	DM5TVS3	Approved	Integrin beta-1-binding protein 1 (ITGB1BP1) affects the response to substance of Vinblastine.	[18]

12 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 Integrin beta-1-binding protein 1 (ITGB1BP1).	[5]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[6]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[8]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[9]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[10]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[11]
Heroin diacetylmorphine	DMDBWHY	Approved	Heroin diacetylmorphine increases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[16]
Nitrobenzanthrone	DMN6L70	Investigative	Nitrobenzanthrone increases the expression of Integrin beta-1-binding protein 1 (ITGB1BP1).	[17]

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 affects the methylation of Integrin beta-1-binding protein 1 (ITGB1BP1).	[13]

References

• [1] Defective osteoblast function in ICAP-1-deficient mice.Development. 2007 Jul;134(14):2615-25. doi: 10.1242/dev.000877. Epub 2007 Jun 13.
• [2] Nuclear Localization of Integrin Cytoplasmic Domain-associated Protein-1 (ICAP1) Influences 1 Integrin Activation and Recruits Krev/Interaction Trapped-1 (KRIT1) to the Nucleus.J Biol Chem. 2017 Feb 3;292(5):1884-1898. doi: 10.1074/jbc.M116.762393. Epub 2016 Dec 21.
• [3] Effects of Type 2 Diabetes Mellitus on Gene Expressions of Mouse Meibomian Glands.Curr Eye Res. 2020 Jan;45(1):72-80. doi: 10.1080/02713683.2019.1656750. Epub 2019 Aug 27.
• [4] In vivo adhesion of malignant B cells to bone marrow microvasculature is regulated by 41 cytoplasmic-binding proteins.Leukemia. 2016 Apr;30(4):861-72. doi: 10.1038/leu.2015.332. Epub 2015 Dec 10.
• [5] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [6] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] 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.
• [8] 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.
• [9] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [10] Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. J Neurochem. 2004 Mar;88(5):1211-9. doi: 10.1046/j.1471-4159.2003.02247.x.
• [11] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [12] Distinctive profiles of gene expression in the human nucleus accumbens associated with cocaine and heroin abuse. Neuropsychopharmacology. 2006 Oct;31(10):2304-12. doi: 10.1038/sj.npp.1301089. Epub 2006 May 3.
• [13] 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.
• [14] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [15] 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.
• [16] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [17] 3-Nitrobenzanthrone promotes malignant transformation in human lung epithelial cells through the epiregulin-signaling pathway. Cell Biol Toxicol. 2022 Oct;38(5):865-887. doi: 10.1007/s10565-021-09612-1. Epub 2021 May 25.
• [18] 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.