Details of Drug Off-Target (DOT)

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

• DOT Name: GRB2-associated and regulator of MAPK protein 1 (GAREM1)
• Synonyms: GRB2-associated and regulator of MAPK1
• Gene Name: GAREM1
• Related Disease:
  Breast carcinoma
  Neoplasm
  Stomach cancer
• UniProt ID: GARE1_HUMAN
• PDB ID: 2DKZ
• Pfam ID: PF12736
• Sequence:
  MDPAPSLGCSLKDVKWSSVAVPLDLLVSTYRLPQIARLDNGECVEGLRENDYLLIHSCRQ
  WTTITAHSLEEGHYVIGPKIEIPVHYAGQFKLLEQDRDIKEPVQYFNSVEEVAKAFPERV
  YVMEDITFNVKVASGECNEDTEVYNITLCTGDELTLMGQAEILYAKTFKEKSRLNTIFKK
  IGKLNSISKLGKGKMPCLICMNHRTNESISLPFQCKGRFSTRSPLELQMQEGEHTIRNIV
  EKTRLPVNVTVPSPPPRNPYDLHFIREGHRYKFVNIQTKTVVVCCVLRNNKILPMHFPLH
  LTVPKFSLPEHLVKGESWPETLVHHWLGICQEQFDIDEYSRAVRDVKTDWNEECKSPKKG
  RCSGHNHVPNSLSYARDELTQSFHRLSVCVYGNNLHGNSEVNLHGCRDLGGDWAPFPHDI
  LPYQDSGDSGSDYLFPEASEESAGIPGKSELPYEELWLEEGKPSHQPLTRSLSEKNRCDQ
  FRGSVRSKCATSPLPIPGTLGAAVKSSDTALPPPPVPPKSEAVREECRLLNAPPVPPRSA
  KPLSTSPSIPPRTVKPARQQTRSPSPTLSYYSSGLHNISVTKTDTNPSESTPVSCYPCNR
  VKTDSVDLKSPFGSPSAEAVSSRLSWPNHYSGASESQTRSDFLLDPSRSYSYPRQKTPGT
  PKRNCPAPFDFDGCELLASPTSPVTAEFSSSVSGCPKSASYSLESTDVKSLAAGVTKQST
  SCPALPPRAPKLVEEKVASETSPLPLKIDGAEEDPKSGSPDLSEDQYFVKKGMQDIFSAS
  YPFSSPLHLQLAPRSCGDGSPWQPPADLSGLSIEEVSKSLRFIGLSEDVISFFVTEKIDG
  NLLVQLTEEILSEDFKLSKLQVKKIMQFINGWRPKI
• Function: [Isoform 1]: Acts as an adapter protein that plays a role in intracellular signaling cascades triggered either by the cell surface activated epidermal growth factor receptor and/or cytoplasmic protein tyrosine kinases. Promotes activation of the MAPK/ERK signaling pathway. Plays a role in the regulation of cell proliferation.
• Tissue Specificity: Isoform 1 is ubiquitously expressed.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[1]
Neoplasm	DISZKGEW	Limited	Altered Expression	[2]
Stomach cancer	DISKIJSX	Limited	Biomarker	[2]

16 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 GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[8]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[11]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[14]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[18]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of GRB2-associated and regulator of MAPK protein 1 (GAREM1).	[17]

References

• [1] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [2] MicroRNA-128 contributes to the progression of gastric carcinoma through GAREM-mediated MAPK signaling activation.Biochem Biophys Res Commun. 2018 Sep 26;504(1):295-301. doi: 10.1016/j.bbrc.2018.08.177. Epub 2018 Aug 31.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [5] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [12] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.