Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT80QNR5)

• DOT Name: Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1)
• Synonyms: TGF-beta receptor-associated protein 1; TRAP-1; TRAP1
• Gene Name: TGFBRAP1
• Related Disease:
  Neoplasm
  Advanced cancer
  Essential hypertension
  High blood pressure
  Non-insulin dependent diabetes
  Schizophrenia
  Squamous cell carcinoma
  Colorectal carcinoma
  Coronary heart disease
  Hepatitis C virus infection
  Hepatocellular carcinoma
• UniProt ID: TGFA1_HUMAN
• Pfam ID: PF00637 ; PF00780 ; PF10366 ; PF10367
• Sequence:
  MMSIKAFTLVSAVERELLMGDKERVNIECVECCGRDLYVGTNDCFVYHFLLEERPVPAGP
  ATFTATKQLQRHLGFKKPVNELRAASALNRLLVLCDNSISLVNMLNLEPVPSGARIKGAA
  TFALNENPVSGDPFCVEVCIISVKRRTIQMFLVYEDRVQIVKEVSTAEQPLAVAVDGHFL
  CLALTTQYIIHNYSTGVSQDLFPYCSEERPPIVKRIGRQEFLLAGPGGLGMFATVAGISQ
  RAPVHWSENVIGAAVSFPYVIALDDEFITVHSMLDQQQKQTLPFKEGHILQDFEGRVIVA
  TSKGVYILVPLPLEKQIQDLLASRRVEEALVLAKGARRNIPKEKFQVMYRRILQQAGFIQ
  FAQLQFLEAKELFRSGQLDVRELISLYPFLLPTSSSFTRSHPPLHEYADLNQLTQGDQEK
  MAKCKRFLMSYLNEVRSTEVANGYKEDIDTALLKLYAEADHDSLLDLLVTENFCLLTDSA
  AWLEKHKKYFALGLLYHYNNQDAAAVQLWVNIVNGDVQDSTRSDLYEYIVDFLTYCLDEE
  LVWAYADWVLQKSEEVGVQVFTKRPLDEQQKNSFNPDDIINCLKKYPKALVKYLEHLVID
  KRLQKEEYHTHLAVLYLEEVLLQRASASGKGAEATETQAKLRRLLQKSDLYRVHFLLERL
  QGAGLPMESAILHGKLGEHEKALHILVHELQDFAAAEDYCLWCSEGRDPPHRQQLFHTLL
  AIYLHAGPTAHELAVAAVDLLNRHATEFDAAQVLQMLPDTWSVQLLCPFLMGAMRDSIHA
  RRTMQVALGLARSENLIYTYDKMKLKGSSIQLSDKKLCQICQNPFCEPVFVRYPNGGLVH
  THCAASRHTNPSSSSPGTRT
• Function: Plays a role in the TGF-beta/activin signaling pathway. It associates with inactive heteromeric TGF-beta and activin receptor complexes, mainly through the type II receptor, and is released upon activation of signaling. May recruit SMAD4 to the vicinity of the receptor complex and facilitate its interaction with receptor-regulated Smads, such as SMAD2; Plays a role in vesicle-mediated protein trafficking of the endocytic membrane transport pathway. Believed to act as a component of the putative CORVET endosomal tethering complexes which is proposed to be involved in the Rab5-to-Rab7 endosome conversion probably implicating MON1A/B, and via binding SNAREs and SNARE complexes to mediate tethering and docking events during SNARE-mediated membrane fusion. The CORVET complex is proposed to function as a Rab5 effector to mediate early endosome fusion probably in specific endosome subpopulations. Functions predominantly in APPL1-containing endosomes and in degradative but not recycling trafficking of endocytosed cargo.
• KEGG Pathway: Efferocytosis (hsa04148)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Essential hypertension	DIS7WI98	Strong	Biomarker	[3]
High blood pressure	DISY2OHH	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[4]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[5]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[6]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[2]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[7]
Hepatitis C virus infection	DISQ0M8R	Limited	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[8]

7 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 Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1).	[9]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1).	[11]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat affects the expression of Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Transforming growth factor-beta receptor-associated protein 1 (TGFBRAP1).	[15]

References

• [1] Correlation between mitochondrial TRAP-1 expression and lymph node metastasis in colorectal cancer.World J Gastroenterol. 2012 Nov 7;18(41):5965-71. doi: 10.3748/wjg.v18.i41.5965.
• [2] Overexpression of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 is associated with the poor prognosis of patients with colorectal cancer.Oncol Lett. 2018 Apr;15(4):5451-5458. doi: 10.3892/ol.2018.8042. Epub 2018 Feb 13.
• [3] Polymorphisms of the TGFBRAP1 gene in relation to blood pressure variability and plasma TGF-1.Clin Exp Hypertens. 2015;37(5):420-5. doi: 10.3109/10641963.2015.1013113. Epub 2015 Apr 9.
• [4] The variant at TGFBRAP1 is significantly associated with type 2 diabetes mellitus and affects diabetes-related miRNA expression.J Cell Mol Med. 2019 Jan;23(1):83-92. doi: 10.1111/jcmm.13885. Epub 2018 Nov 20.
• [5] Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.Am J Hum Genet. 2019 Aug 1;105(2):334-350. doi: 10.1016/j.ajhg.2019.06.012.
• [6] Variations of chromosome 2 gene expressions among patients with lung cancer or non-cancer.Cell Biol Toxicol. 2016 Oct;32(5):419-35. doi: 10.1007/s10565-016-9343-z. Epub 2016 Jun 15.
• [7] Genetic evidence for PLASMINOGEN as a shared genetic risk factor of coronary artery disease and periodontitis.Circ Cardiovasc Genet. 2015 Feb;8(1):159-67. doi: 10.1161/CIRCGENETICS.114.000554. Epub 2014 Dec 2.
• [8] Hepatitis C virus core impacts expression of miR122 and miR204 involved in carcinogenic progression via regulation of TGFBRAP1 and HOTTIP expression.Onco Targets Ther. 2018 Mar 2;11:1173-1182. doi: 10.2147/OTT.S149254. eCollection 2018.
• [9] 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.
• [10] 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.
• [11] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [12] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [13] The Bromodomain Inhibitor JQ1 and the Histone Deacetylase Inhibitor Panobinostat Synergistically Reduce N-Myc Expression and Induce Anticancer Effects. Clin Cancer Res. 2016 May 15;22(10):2534-44. doi: 10.1158/1078-0432.CCR-15-1666. Epub 2016 Jan 5.
• [14] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [15] Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Lab Anim Res. 2011 Jun;27(2):99-107. doi: 10.5625/lar.2011.27.2.99. Epub 2011 Jun 22.