Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTOP7LTE)

• DOT Name: Growth factor receptor-bound protein 2 (GRB2)
• Synonyms: Adapter protein GRB2; Protein Ash; SH2/SH3 adapter GRB2
• Gene Name: GRB2
• UniProt ID: GRB2_HUMAN
• PDB ID: 1AZE ; 1BM2 ; 1BMB ; 1CJ1 ; 1FHS ; 1FYR ; 1GCQ ; 1GFC ; 1GFD ; 1GHU ; 1GRI ; 1IO6 ; 1JYQ ; 1JYR ; 1JYU ; 1QG1 ; 1TZE ; 1X0N ; 1ZFP ; 2AOA ; 2AOB ; 2H46 ; 2H5K ; 2HUW ; 2VVK ; 2VWF ; 2W0Z ; 3C7I ; 3IMD ; 3IMJ ; 3IN7 ; 3IN8 ; 3KFJ ; 3MXC ; 3MXY ; 3N7Y ; 3N84 ; 3N8M ; 3OV1 ; 3OVE ; 3S8L ; 3S8N ; 3S8O ; 3WA4 ; 4P9V ; 4P9Z ; 5CDW ; 6ICG ; 6ICH ; 6SDF ; 6VK2 ; 6WM1 ; 6WO2 ; 7MPH
• Pfam ID: PF00017 ; PF00018
• Sequence:
  MEAIAKYDFKATADDELSFKRGDILKVLNEECDQNWYKAELNGKDGFIPKNYIEMKPHPW
  FFGKIPRAKAEEMLSKQRHDGAFLIRESESAPGDFSLSVKFGNDVQHFKVLRDGAGKYFL
  WVVKFNSLNELVDYHRSTSVSRNQQIFLRDIEQVPQQPTYVQALFDFDPQEDGELGFRRG
  DFIHVMDNSDPNWWKGACHGQTGMFPRNYVTPVNRNV
• Function: Adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway; [Isoform 2]: Does not bind to phosphorylated epidermal growth factor receptor (EGFR) but inhibits EGF-induced transactivation of a RAS-responsive element. Acts as a dominant negative protein over GRB2 and by suppressing proliferative signals, may trigger active programmed cell death.
• KEGG Pathway:
  EGFR tyrosine ki.se inhibitor resistance (hsa01521)
  Endocrine resistance (hsa01522)
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  FoxO sig.ling pathway (hsa04068)
  Phospholipase D sig.ling pathway (hsa04072)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  Osteoclast differentiation (hsa04380)
  Focal adhesion (hsa04510)
  Gap junction (hsa04540)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  JAK-STAT sig.ling pathway (hsa04630)
  .tural killer cell mediated cytotoxicity (hsa04650)
  T cell receptor sig.ling pathway (hsa04660)
  B cell receptor sig.ling pathway (hsa04662)
  Fc epsilon RI sig.ling pathway (hsa04664)
  Thermogenesis (hsa04714)
  Neurotrophin sig.ling pathway (hsa04722)
  Insulin sig.ling pathway (hsa04910)
  GnRH sig.ling pathway (hsa04912)
  Estrogen sig.ling pathway (hsa04915)
  Prolactin sig.ling pathway (hsa04917)
  Relaxin sig.ling pathway (hsa04926)
  Growth hormone synthesis, secretion and action (hsa04935)
  Alcoholism (hsa05034)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Proteoglycans in cancer (hsa05205)
  MicroR.s in cancer (hsa05206)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Chemical carcinogenesis - reactive oxygen species (hsa05208)
  Colorectal cancer (hsa05210)
  Re.l cell carcinoma (hsa05211)
  Endometrial cancer (hsa05213)
  Glioma (hsa05214)
  Prostate cancer (hsa05215)
  Chronic myeloid leukemia (hsa05220)
  Acute myeloid leukemia (hsa05221)
  Non-small cell lung cancer (hsa05223)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  (Name not found)
  Signaling by CSF3 (G-CSF) (R-HSA-9674555)
  STAT5 activation downstream of FLT3 ITD mutants (R-HSA-9702518)
  Signaling by FLT3 ITD and TKD mutants (R-HSA-9703648)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Interleukin-15 signaling (R-HSA-8983432)

Molecular Interaction Atlas (MIA) of This DOT

22 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 Growth factor receptor-bound protein 2 (GRB2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[2]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[5]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Growth factor receptor-bound protein 2 (GRB2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[9]
Hydroquinone	DM6AVR4	Approved	Hydroquinone affects the expression of Growth factor receptor-bound protein 2 (GRB2).	[10]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[11]
Acocantherin	DM7JT24	Approved	Acocantherin decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[12]
Sorafenib	DMS8IFC	Approved	Sorafenib decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[13]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[14]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[13]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[16]
Tetrandrine	DMAOJBX	Phase 1	Tetrandrine decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Growth factor receptor-bound protein 2 (GRB2).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[20]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[21]
Chrysin	DM7V2LG	Investigative	Chrysin decreases the expression of Growth factor receptor-bound protein 2 (GRB2).	[22]

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 Growth factor receptor-bound protein 2 (GRB2).	[17]

References

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• [2] 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.
• [3] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [4] Estrogen Regulates MAPK-Related Genes through Genomic and Nongenomic Interactions between IGF-I Receptor Tyrosine Kinase and Estrogen Receptor-Alpha Signaling Pathways in Human Uterine Leiomyoma Cells. J Signal Transduct. 2012;2012:204236. doi: 10.1155/2012/204236. Epub 2012 Oct 9.
• [5] 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.
• [6] Quercetin and Cisplatin combined treatment altered cell cycle and mitogen activated protein kinase expressions in malignant mesotelioma cells. BMC Complement Altern Med. 2016 Aug 11;16(1):281. doi: 10.1186/s12906-016-1267-x.
• [7] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [8] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [9] 1,25-Dihydroxyvitamin D3 suppresses gene expression of eukaryotic translation initiation factor 2 in human promyelocytic leukemia HL-60 cells. Cell Struct Funct. 2005;30(1):1-6. doi: 10.1247/csf.30.1.
• [10] Proteomic analysis to identify the cellular responses induced by hydroquinone in human embryonic lung fibroblasts. Toxicol Mech Methods. 2006;16(1):1-6. doi: 10.1080/15376520500191797.
• [11] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [12] Ouabain impairs cell migration, and invasion and alters gene expression of human osteosarcoma U-2 OS cells. Environ Toxicol. 2017 Nov;32(11):2400-2413. doi: 10.1002/tox.22453. Epub 2017 Aug 10.
• [13] Novel carbocyclic curcumin analog CUR3d modulates genes involved in multiple apoptosis pathways in human hepatocellular carcinoma cells. Chem Biol Interact. 2015 Dec 5;242:107-22.
• [14] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [15] Identification of retinoid-modulated proteins in squamous carcinoma cells using high-throughput immunoblotting. Cancer Res. 2004 Apr 1;64(7):2439-48. doi: 10.1158/0008-5472.can-03-2643.
• [16] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [17] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [18] Tetrandrine inhibits human brain glioblastoma multiforme GBM 8401 cancer cell migration and invasion in vitro. Environ Toxicol. 2019 Apr;34(4):364-374. doi: 10.1002/tox.22691. Epub 2018 Dec 13.
• [19] Bisphenol A induces human uterine leiomyoma cell proliferation through membrane-associated ER36 via nongenomic signaling pathways. Mol Cell Endocrinol. 2019 Mar 15;484:59-68. doi: 10.1016/j.mce.2019.01.001. Epub 2019 Jan 4.
• [20] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [21] Gallic acid inhibits migration and invasion in human osteosarcoma U-2 OS cells through suppressing the matrix metalloproteinase-2/-9, protein kinase B (PKB) and PKC signaling pathways. Food Chem Toxicol. 2012 May;50(5):1734-40. doi: 10.1016/j.fct.2012.02.033. Epub 2012 Feb 25.
• [22] Chrysin inhibit human melanoma A375.S2 cell migration and invasion via affecting MAPK signaling and NF-B signaling pathway in vitro. Environ Toxicol. 2019 Apr;34(4):434-442. doi: 10.1002/tox.22697. Epub 2018 Dec 22.