Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO1P7YX)

• DOT Name: GRB2-related adapter protein (GRAP)
• Gene Name: GRAP
• Related Disease:
  Advanced cancer
  Diabetic kidney disease
  Sjogren syndrome
  Head-neck squamous cell carcinoma
  Sensorineural hearing loss disorder
  Hearing loss, autosomal recessive
  Hearing loss, autosomal recessive 114
• UniProt ID: GRAP_HUMAN
• Pfam ID: PF00017 ; PF00018
• Sequence:
  MESVALYSFQATESDELAFNKGDTLKILNMEDDQNWYKAELRGVEGFIPKNYIRVKPHPW
  YSGRISRQLAEEILMKRNHLGAFLIRESESSPGEFSVSVNYGDQVQHFKVLREASGKYFL
  WEEKFNSLNELVDFYRTTTIAKKRQIFLRDEEPLLKSPGACFAQAQFDFSAQDPSQLSFR
  RGDIIEVLERPDPHWWRGRSCGRVGFFPRSYVQPVHL
• Function: Couples signals from receptor and cytoplasmic tyrosine kinases to the Ras signaling pathway. Plays a role in the inner ear and in hearing.
• Reactome Pathway: Signaling by SCF-KIT (R-HSA-1433557)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[2]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[3]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[4]
Sensorineural hearing loss disorder	DISJV45Z	moderate	Genetic Variation	[5]
Hearing loss, autosomal recessive	DIS8G9R9	Supportive	Autosomal recessive	[5]
Hearing loss, autosomal recessive 114	DISTY0KJ	Limited	Autosomal recessive	[5]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of GRB2-related adapter protein (GRAP).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of GRB2-related adapter protein (GRAP).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of GRB2-related adapter protein (GRAP).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of GRB2-related adapter protein (GRAP).	[9]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of GRB2-related adapter protein (GRAP).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of GRB2-related adapter protein (GRAP).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of GRB2-related adapter protein (GRAP).	[12]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of GRB2-related adapter protein (GRAP).	[10]

References

• [1] The Teesside cancer family history service: change management and innovation at cancer network level.Fam Cancer. 2007;6(2):181-7. doi: 10.1007/s10689-007-9125-0. Epub 2007 May 17.
• [2] Quantitative mass spectrometry of diabetic kidney tubules identifies GRAP as a novel regulator of TGF-beta signaling.Biochim Biophys Acta. 2010 Apr;1804(4):653-61. doi: 10.1016/j.bbapap.2009.09.029. Epub 2009 Oct 22.
• [3] Detection of Grb-2-related adaptor protein gene (GRAP) and peptide molecule in salivary glands of MRL/lpr mice and patients with Sjgren's syndrome.J Int Med Res. 2004 May-Jun;32(3):284-91. doi: 10.1177/147323000403200308.
• [4] miR-654-5p Targets GRAP to Promote Proliferation, Metastasis, and Chemoresistance of Oral Squamous Cell Carcinoma Through Ras/MAPK Signaling.DNA Cell Biol. 2018 Apr;37(4):381-388. doi: 10.1089/dna.2017.4095. Epub 2018 Jan 24.
• [5] Dysfunction of GRAP, encoding the GRB2-related adaptor protein, is linked to sensorineural hearing loss. Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1347-1352. doi: 10.1073/pnas.1810951116. Epub 2019 Jan 4.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [11] 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.
• [12] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.