Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDMD800)

DOT Name Fibroblast growth factor receptor substrate 2 (FRS2)
Synonyms FGFR substrate 2; FGFR-signaling adaptor SNT; Suc1-associated neurotrophic factor target 1; SNT-1
Gene Name FRS2
Related Disease
Neoplasm ( )
Arteriosclerosis ( )
Atherosclerosis ( )
Breast cancer ( )
Breast carcinoma ( )
Chordoma ( )
Encephalocraniocutaneous lipomatosis ( )
Epithelial ovarian cancer ( )
Immunodeficiency ( )
Liposarcoma ( )
Melanoma ( )
Multiple endocrine neoplasia ( )
Neuralgia ( )
Non-small-cell lung cancer ( )
Osteosarcoma ( )
Ovarian cancer ( )
Ovarian neoplasm ( )
Pancreatic cancer ( )
Dedifferentiated liposarcoma ( )
Narcolepsy type 1 ( )
Prostate cancer ( )
Prostate carcinoma ( )
Neuroblastoma ( )
Adult lymphoma ( )
Bladder cancer ( )
Bone osteosarcoma ( )
Childhood kidney Wilms tumor ( )
Glaucoma/ocular hypertension ( )
Lymphoma ( )
Pediatric lymphoma ( )
Thyroid gland papillary carcinoma ( )
Urinary bladder cancer ( )
Urinary bladder neoplasm ( )
Wilms tumor ( )
UniProt ID
FRS2_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
1XR0; 2MFQ
Pfam ID
PF02174
Sequence
MGSCCSCPDKDTVPDNHRNKFKVINVDDDGNELGSGIMELTDTELILYTRKRDSVKWHYL
CLRRYGYDSNLFSFESGRRCQTGQGIFAFKCARAEELFNMLQEIMQNNSINVVEEPVVER
NNHQTELEVPRTPRTPTTPGFAAQNLPNGYPRYPSFGDASSHPSSRHPSVGSARLPSVGE
ESTHPLLVAEEQVHTYVNTTGVQEERKNRTSVHVPLEARVSNAESSTPKEEPSSIEDRDP
QILLEPEGVKFVLGPTPVQKQLMEKEKLEQLGRDQVSGSGANNTEWDTGYDSDERRDAPS
VNKLVYENINGLSIPSASGVRRGRLTSTSTSDTQNINNSAQRRTALLNYENLPSLPPVWE
ARKLSRDEDDNLGPKTPSLNGYHNNLDPMHNYVNTENVTVPASAHKIEYSRRRDCTPTVF
NFDIRRPSLEHRQLNYIQVDLEGGSDSDNPQTPKTPTTPLPQTPTRRTELYAVIDIERTA
AMSNLQKALPRDDGTSRKTRHNSTDLPM
Function
Adapter protein that links activated FGR and NGF receptors to downstream signaling pathways. Plays an important role in the activation of MAP kinases and in the phosphorylation of PIK3R1, the regulatory subunit of phosphatidylinositol 3-kinase, in response to ligand-mediated activation of FGFR1. Modulates signaling via SHC1 by competing for a common binding site on NTRK1.
Tissue Specificity Highly expressed in heart, brain, spleen, lung, liver, skeletal muscle, kidney and testis.
KEGG Pathway
Thermogenesis (hsa04714 )
Neurotrophin sig.ling pathway (hsa04722 )
Proteoglycans in cancer (hsa05205 )
Reactome Pathway
PIP3 activates AKT signaling (R-HSA-1257604 )
Frs2-mediated activation (R-HSA-170968 )
Signaling by ALK (R-HSA-201556 )
Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530 )
PI-3K cascade (R-HSA-5654689 )
FRS-mediated FGFR1 signaling (R-HSA-5654693 )
PI-3K cascade (R-HSA-5654695 )
FRS-mediated FGFR2 signaling (R-HSA-5654700 )
FRS-mediated FGFR3 signaling (R-HSA-5654706 )
PI-3K cascade (R-HSA-5654710 )
FRS-mediated FGFR4 signaling (R-HSA-5654712 )
PI-3K cascade (R-HSA-5654720 )
Negative regulation of FGFR1 signaling (R-HSA-5654726 )
Negative regulation of FGFR2 signaling (R-HSA-5654727 )
Negative regulation of FGFR3 signaling (R-HSA-5654732 )
Negative regulation of FGFR4 signaling (R-HSA-5654733 )
Signaling by FGFR2 in disease (R-HSA-5655253 )
Signaling by FGFR4 in disease (R-HSA-5655291 )
Signaling by FGFR1 in disease (R-HSA-5655302 )
Signaling by FGFR3 in disease (R-HSA-5655332 )
RAF/MAP kinase cascade (R-HSA-5673001 )
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558 )
RET signaling (R-HSA-8853659 )
Activated NTRK2 signals through FRS2 and FRS3 (R-HSA-9028731 )
RND2 GTPase cycle (R-HSA-9696270 )
RND1 GTPase cycle (R-HSA-9696273 )
Signaling by ALK fusions and activated point mutants (R-HSA-9725370 )
PI3K Cascade (R-HSA-109704 )

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Neoplasm DISZKGEW Definitive Genetic Variation [1]
Arteriosclerosis DISK5QGC Strong Biomarker [2]
Atherosclerosis DISMN9J3 Strong Biomarker [2]
Breast cancer DIS7DPX1 Strong Biomarker [3]
Breast carcinoma DIS2UE88 Strong Biomarker [3]
Chordoma DISCHJE7 Strong Genetic Variation [4]
Encephalocraniocutaneous lipomatosis DIST7LTP Strong Altered Expression [5]
Epithelial ovarian cancer DIS56MH2 Strong Biomarker [6]
Immunodeficiency DIS093I0 Strong Altered Expression [6]
Liposarcoma DIS8IZVM Strong Biomarker [7]
Melanoma DIS1RRCY Strong Biomarker [8]
Multiple endocrine neoplasia DISZGBKW Strong Genetic Variation [9]
Neuralgia DISWO58J Strong Biomarker [10]
Non-small-cell lung cancer DIS5Y6R9 Strong Biomarker [11]
Osteosarcoma DISLQ7E2 Strong Biomarker [12]
Ovarian cancer DISZJHAP Strong Biomarker [6]
Ovarian neoplasm DISEAFTY Strong Biomarker [6]
Pancreatic cancer DISJC981 Strong Biomarker [13]
Dedifferentiated liposarcoma DISYJUCJ moderate Biomarker [14]
Narcolepsy type 1 DISH7Y6Q moderate Altered Expression [15]
Prostate cancer DISF190Y moderate Biomarker [16]
Prostate carcinoma DISMJPLE moderate Biomarker [16]
Neuroblastoma DISVZBI4 Disputed Altered Expression [17]
Adult lymphoma DISK8IZR Limited Biomarker [18]
Bladder cancer DISUHNM0 Limited Genetic Variation [1]
Bone osteosarcoma DIST1004 Limited Genetic Variation [19]
Childhood kidney Wilms tumor DIS0NMK3 Limited Biomarker [20]
Glaucoma/ocular hypertension DISLBXBY Limited Biomarker [21]
Lymphoma DISN6V4S Limited Biomarker [18]
Pediatric lymphoma DIS51BK2 Limited Biomarker [18]
Thyroid gland papillary carcinoma DIS48YMM Limited Biomarker [22]
Urinary bladder cancer DISDV4T7 Limited Genetic Variation [1]
Urinary bladder neoplasm DIS7HACE Limited Genetic Variation [1]
Wilms tumor DISB6T16 Limited Biomarker [20]
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⏷ Show the Full List of 34 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
9 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 Fibroblast growth factor receptor substrate 2 (FRS2). [23]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [24]
Quercetin DM3NC4M Approved Quercetin increases the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [25]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [26]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [27]
Diclofenac DMPIHLS Approved Diclofenac affects the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [27]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [30]
Trichostatin A DM9C8NX Investigative Trichostatin A affects the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [32]
Formaldehyde DM7Q6M0 Investigative Formaldehyde decreases the expression of Fibroblast growth factor receptor substrate 2 (FRS2). [33]
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⏷ Show the Full List of 9 Drug(s)
5 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
AZD4547 DM3827C Phase 2/3 AZD4547 increases the phosphorylation of Fibroblast growth factor receptor substrate 2 (FRS2). [28]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the methylation of Fibroblast growth factor receptor substrate 2 (FRS2). [29]
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 decreases the phosphorylation of Fibroblast growth factor receptor substrate 2 (FRS2). [31]
Coumarin DM0N8ZM Investigative Coumarin decreases the phosphorylation of Fibroblast growth factor receptor substrate 2 (FRS2). [31]
Hexadecanoic acid DMWUXDZ Investigative Hexadecanoic acid decreases the phosphorylation of Fibroblast growth factor receptor substrate 2 (FRS2). [34]
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References

1 Whole-genome sequencing identifies ADGRG6 enhancer mutations and FRS2 duplications as angiogenesis-related drivers in bladder cancer.Nat Commun. 2019 Feb 12;10(1):720. doi: 10.1038/s41467-019-08576-5.
2 Endothelial-to-mesenchymal transition drives atherosclerosis progression.J Clin Invest. 2015 Oct 26;125(12):4514-28. doi: 10.1172/JCI82719.
3 Expression of the SNT-1/FRS2 phosphotyrosine binding domain inhibits activation of MAP kinase and PI3-kinase pathways and antiestrogen resistant growth induced by FGF-1 in human breast carcinoma cells.Oncogene. 2006 Sep 28;25(44):6003-14. doi: 10.1038/sj.onc.1209592. Epub 2006 May 8.
4 Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas.Mod Pathol. 2009 Aug;22(8):996-1005. doi: 10.1038/modpathol.2009.63. Epub 2009 May 1.
5 Mosaic Activating Mutations in FGFR1 Cause Encephalocraniocutaneous Lipomatosis. Am J Hum Genet. 2016 Mar 3;98(3):579-587. doi: 10.1016/j.ajhg.2016.02.006.
6 The Tyrosine Kinase Adaptor Protein FRS2 Is Oncogenic and Amplified in High-Grade Serous Ovarian Cancer.Mol Cancer Res. 2015 Mar;13(3):502-9. doi: 10.1158/1541-7786.MCR-14-0407. Epub 2014 Nov 3.
7 Preclinical Evaluation of the Pan-FGFR Inhibitor LY2874455 in FRS2-Amplified Liposarcoma.Cells. 2019 Feb 21;8(2):189. doi: 10.3390/cells8020189.
8 Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma.PLoS One. 2011 Apr 8;6(4):e18369. doi: 10.1371/journal.pone.0018369.
9 Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction.Oncogene. 2001 Apr 12;20(16):1929-38. doi: 10.1038/sj.onc.1204290.
10 Blockade of anoctamin-1 in injured and uninjured nerves reduces neuropathic pain.Brain Res. 2018 Oct 1;1696:38-48. doi: 10.1016/j.brainres.2018.06.001. Epub 2018 Jun 2.
11 Combined use of salivary biomarkers and carcinoembryonic antigen for lung cancer detection in a Chinese population.Medicine (Baltimore). 2019 Aug;98(31):e16511. doi: 10.1097/MD.0000000000016511.
12 Amplification of FRS2 in atypical lipomatous tumour/well-differentiated liposarcoma and de-differentiated liposarcoma: a clinicopathological and genetic study of 146 cases.Histopathology. 2018 Jun;72(7):1145-1155. doi: 10.1111/his.13473. Epub 2018 Mar 7.
13 Enhanced FGFR signalling predisposes pancreatic cancer to the effect of a potent FGFR inhibitor in preclinical models.Br J Cancer. 2014 Jan 21;110(2):320-9. doi: 10.1038/bjc.2013.754. Epub 2013 Dec 10.
14 Consistent Amplification of FRS2 and MDM2 in Low-grade Osteosarcoma: A Genetic Study of 22 Cases With Clinicopathologic Analysis.Am J Surg Pathol. 2018 Sep;42(9):1143-1155. doi: 10.1097/PAS.0000000000001125.
15 Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling.EBioMedicine. 2018 Mar;29:47-59. doi: 10.1016/j.ebiom.2018.01.043. Epub 2018 Feb 2.
16 Role and expression of FRS2 and FRS3 in prostate cancer.BMC Cancer. 2011 Nov 11;11:484. doi: 10.1186/1471-2407-11-484.
17 Genomic coamplification of CDK4/MDM2/FRS2 is associated with very poor prognosis and atypical clinical features in neuroblastoma patients.Genes Chromosomes Cancer. 2020 May;59(5):277-285. doi: 10.1002/gcc.22827. Epub 2019 Dec 3.
18 Expression of interleukin-9 in nasal natural killer/T-cell lymphoma cell lines and patients.Clin Cancer Res. 2005 Dec 1;11(23):8250-7. doi: 10.1158/1078-0432.CCR-05-1426.
19 Identification of miRNA and genes involving in osteosarcoma by comprehensive analysis of microRNA and copy number variation data.Oncol Lett. 2017 Nov;14(5):5427-5433. doi: 10.3892/ol.2017.6845. Epub 2017 Aug 28.
20 MicroRNA-613 attenuates the proliferation, migration and invasion of Wilms' tumor via targeting FRS2.Eur Rev Med Pharmacol Sci. 2017 Aug;21(15):3360-3369.
21 Intraocular miR-211 exacerbates pressure-induced cell death in retinal ganglion cells via direct repression of FRS2 signaling.Biochem Biophys Res Commun. 2018 Sep 18;503(4):2984-2992. doi: 10.1016/j.bbrc.2018.08.082. Epub 2018 Aug 18.
22 Docking protein FRS2 links the protein tyrosine kinase RET and its oncogenic forms with the mitogen-activated protein kinase signaling cascade.Mol Cell Biol. 2001 Jul;21(13):4177-87. doi: 10.1128/MCB.21.13.4177-4187.2001.
23 From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
24 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.
25 Quercetin induced cell apoptosis and altered gene expression in AGS human gastric cancer cells. Environ Toxicol. 2018 Nov;33(11):1168-1181. doi: 10.1002/tox.22623. Epub 2018 Aug 27.
26 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.
27 Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
28 Inhibition of cholesterol metabolism underlies synergy between mTOR pathway inhibition and chloroquine in bladder cancer cells. Oncogene. 2016 Aug 25;35(34):4518-28. doi: 10.1038/onc.2015.511. Epub 2016 Feb 8.
29 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.
30 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.
31 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.
32 A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
33 Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
34 Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.