Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7VZ2IZ)

• DOT Name: ERBB receptor feedback inhibitor 1 (ERRFI1)
• Synonyms: Mitogen-inducible gene 6 protein; MIG-6
• Gene Name: ERRFI1
• Related Disease:
  Lung adenocarcinoma
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Angiosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Diabetic kidney disease
  Endometrial cancer
  Endometrial carcinoma
  Endometrium adenocarcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Intervertebral disc degeneration
  Lung cancer
  Lung neoplasm
  Neoplasm
  Non-insulin dependent diabetes
  Polycystic ovarian syndrome
  Skin neoplasm
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Colorectal carcinoma
  Lung carcinoma
  Neuroblastoma
  Non-small-cell lung cancer
  Endometriosis
  Hyperglycemia
  Melanoma
  Metastatic malignant neoplasm
  Type-1 diabetes
  Type-1/2 diabetes
• UniProt ID: ERRFI_HUMAN
• PDB ID: 2RF9; 2RFD; 2RFE; 4I21; 4R3P; 4R3R; 4ZJV
• Pfam ID: PF09027 ; PF11555
• Sequence:
  MSIAGVAAQEIRVPLKTGFLHNGRAMGNMRKTYWSSRSEFKNNFLNIDPITMAYSLNSSA
  QERLIPLGHASKSAPMNGHCFAENGPSQKSSLPPLLIPPSENLGPHEEDQVVCGFKKLTV
  NGVCASTPPLTPIKNSPSLFPCAPLCERGSRPLPPLPISEALSLDDTDCEVEFLTSSDTD
  FLLEDSTLSDFKYDVPGRRSFRGCGQINYAYFDTPAVSAADLSYVSDQNGGVPDPNPPPP
  QTHRRLRRSHSGPAGSFNKPAIRISNCCIHRASPNSDEDKPEVPPRVPIPPRPVKPDYRR
  WSAEVTSSTYSDEDRPPKVPPREPLSPSNSRTPSPKSLPSYLNGVMPPTQSFAPDPKYVS
  SKALQRQNSEGSASKVPCILPIIENGKKVSSTHYYLLPERPPYLDKYEKFFREAEETNGG
  AQIQPLPADCGISSATEKPDSKTKMDLGGHVKRKHLSYVVSP
• Function: Negative regulator of EGFR signaling in skin morphogenesis. Acts as a negative regulator for several EGFR family members, including ERBB2, ERBB3 and ERBB4. Inhibits EGFR catalytic activity by interfering with its dimerization. Inhibits autophosphorylation of EGFR, ERBB2 and ERBB4. Important for normal keratinocyte proliferation and differentiation. Plays a role in modulating the response to steroid hormones in the uterus. Required for normal response to progesterone in the uterus and for fertility. Mediates epithelial estrogen responses in the uterus by regulating ESR1 levels and activation. Important for regulation of endometrium cell proliferation. Important for normal prenatal and perinatal lung development.

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Angiosarcoma	DISIYS9W	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[8]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[9]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[9]
Endometrium adenocarcinoma	DISY6744	Strong	Biomarker	[10]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[12]
Intervertebral disc degeneration	DISG3AIM	Strong	Altered Expression	[13]
Lung cancer	DISCM4YA	Strong	Biomarker	[14]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[16]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[17]
Thyroid cancer	DIS3VLDH	Strong	Biomarker	[18]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[18]
Thyroid tumor	DISLVKMD	Strong	Biomarker	[18]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[19]
Lung carcinoma	DISTR26C	moderate	Biomarker	[14]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[20]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[21]
Endometriosis	DISX1AG8	Disputed	Biomarker	[22]
Hyperglycemia	DIS0BZB5	Limited	Biomarker	[23]
Melanoma	DIS1RRCY	Limited	Altered Expression	[24]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[25]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[26]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of ERBB receptor feedback inhibitor 1 (ERRFI1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of ERBB receptor feedback inhibitor 1 (ERRFI1).	[51]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[29]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[32]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[33]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[34]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[35]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[36]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[36]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[37]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[38]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[39]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[22]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[41]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[42]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[43]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[44]
2-deoxyglucose	DMIAHVU	Approved	2-deoxyglucose decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[44]
Bleomycin	DMNER5S	Approved	Bleomycin decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[44]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[45]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[46]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[34]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[47]
MGCD-0103	DM726HX	Phase 2	MGCD-0103 increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[44]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[48]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[49]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[50]
Tacedinaline	DM1Z74X	Discontinued in Phase 2	Tacedinaline increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[44]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[52]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[53]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[54]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[55]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[34]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of ERBB receptor feedback inhibitor 1 (ERRFI1).	[56]

References

• [1] Phosphorylation of Mig6 negatively regulates the ubiquitination and degradation of EGFR mutants in lung adenocarcinoma cell lines.Cell Signal. 2018 Mar;43:21-31. doi: 10.1016/j.cellsig.2017.11.006. Epub 2017 Dec 2.
• [2] Mig-6 deficiency cooperates with oncogenic Kras to promote mouse lung tumorigenesis.Lung Cancer. 2017 Oct;112:47-56. doi: 10.1016/j.lungcan.2017.08.001. Epub 2017 Aug 5.
• [3] microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma.Cancer Res. 2014 Mar 1;74(5):1541-53. doi: 10.1158/0008-5472.CAN-13-1449. Epub 2014 Jan 14.
• [4] MEF2C promotes gefitinib resistance in hepatic cancer cells through regulating MIG6 transcription.Tumori. 2018 Jun;104(3):221-231. doi: 10.1177/0300891618765555. Epub 2018 Apr 11.
• [5] Identification of potential target genes associated with the effect of propranolol on angiosarcoma via microarray analysis.Oncol Lett. 2017 Jun;13(6):4267-4275. doi: 10.3892/ol.2017.5968. Epub 2017 Mar 31.
• [6] Tocotrienol-treated MCF-7 human breast cancer cells show down-regulation of API5 and up-regulation of MIG6 genes.Cancer Genomics Proteomics. 2011 Jan-Feb;8(1):19-31.
• [7] Loss of RALT/MIG-6 expression in ERBB2-amplified breast carcinomas enhances ErbB-2 oncogenic potency and favors resistance to Herceptin.Oncogene. 2005 Jun 30;24(28):4540-8. doi: 10.1038/sj.onc.1208658.
• [8] Novel ERBB receptor feedback inhibitor 1 (ERRFI1) + 808 T/G polymorphism confers protective effect on diabetic nephropathy in a Korean population.Dis Markers. 2013;34(2):113-24. doi: 10.3233/DMA-120949.
• [9] Mig-6 Mouse Model of Endometrial Cancer.Adv Exp Med Biol. 2017;943:243-259. doi: 10.1007/978-3-319-43139-0_8.
• [10] Mig-6 modulates uterine steroid hormone responsiveness and exhibits altered expression in endometrial disease.Proc Natl Acad Sci U S A. 2009 May 26;106(21):8677-82. doi: 10.1073/pnas.0903632106. Epub 2009 May 13.
• [11] Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.Nat Struct Mol Biol. 2015 Sep;22(9):703-711. doi: 10.1038/nsmb.3074. Epub 2015 Aug 17.
• [12] MicroRNA-374a Promotes Hepatocellular Carcinoma Cell Proliferation by Targeting Mitogen-Inducible Gene 6 (MIG-6).Oncol Res. 2018 May 7;26(4):557-563. doi: 10.3727/096504017X15000784459799. Epub 2017 Jul 21.
• [13] ERRFI1 Inhibits Proliferation and Inflammation of Nucleus Pulposus and Is Negatively Regulated by miR-2355-5p in Intervertebral Disc Degeneration.Spine (Phila Pa 1976). 2019 Aug 1;44(15):E873-E881. doi: 10.1097/BRS.0000000000003011.
• [14] Conversion of MIG6 peptide from the nonbinder to binder of lung cancer-related EGFR by phosphorylation and cyclization.Artif Cells Nanomed Biotechnol. 2017 Aug;45(5):1023-1028. doi: 10.1080/21691401.2016.1200058. Epub 2016 Jun 25.
• [15] A calcium-dependent phospholipase A2 (cPLA2) expression is regulated by MIG-6 during endometrial tumorigenesis.Biochem Biophys Res Commun. 2019 Mar 26;511(1):129-134. doi: 10.1016/j.bbrc.2019.02.034. Epub 2019 Feb 14.
• [16] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [17] Mig6 is a negative regulator of EGF receptor-mediated skin morphogenesis and tumor formation.Nat Med. 2006 May;12(5):568-73. doi: 10.1038/nm1401. Epub 2006 Apr 30.
• [18] Mitogen-inducible gene-6 is a multifunctional adaptor protein with tumor suppressor-like activity in papillary thyroid cancer.J Clin Endocrinol Metab. 2011 Mar;96(3):E554-65. doi: 10.1210/jc.2010-1800. Epub 2010 Dec 29.
• [19] Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation.J Cell Physiol. 2020 Feb;235(2):1576-1587. doi: 10.1002/jcp.29076. Epub 2019 Jul 16.
• [20] Genetic and epigenetic changes in the common 1p36 deletion in neuroblastoma tumours. Br J Cancer. 2007 Nov 19;97(10):1416-24. doi: 10.1038/sj.bjc.6604032. Epub 2007 Oct 16.
• [21] Lung cancer stem cells and their aggressive progeny, controlled by EGFR/MIG6 inverse expression, dictate a novel NSCLC treatment approach.Oncotarget. 2019 Apr 2;10(26):2546-2560. doi: 10.18632/oncotarget.26817. eCollection 2019 Apr 2.
• [22] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [23] Role of Mig-6 in hepatic glucose metabolism.J Diabetes. 2016 Jan;8(1):86-97. doi: 10.1111/1753-0407.12261. Epub 2015 Mar 24.
• [24] MIG6 Is MEK Regulated and Affects EGF-Induced Migration in Mutant NRAS Melanoma.J Invest Dermatol. 2016 Feb;136(2):453-463. doi: 10.1016/j.jid.2015.11.012. Epub 2015 Nov 20.
• [25] Mitogen Inducible Gene-6 Is a Prognostic Marker for Patients with Colorectal Liver Metastases.Transl Oncol. 2019 Mar;12(3):550-560. doi: 10.1016/j.tranon.2018.12.007. Epub 2019 Jan 9.
• [26] Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes.Diabetologia. 2014 Oct;57(10):2066-75. doi: 10.1007/s00125-014-3311-z. Epub 2014 Jul 4.
• [27] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] 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.
• [32] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [33] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [34] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [35] 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.
• [36] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [37] 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.
• [38] Decitabine up-regulates S100A2 expression and synergizes with IFN-gamma to kill uveal melanoma cells. Clin Cancer Res. 2007 Sep 1;13(17):5219-25. doi: 10.1158/1078-0432.CCR-07-0816.
• [39] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [40] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [41] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [42] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [43] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [44] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [45] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [46] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [47] Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF. EMBO J. 2009 Mar 4;28(5):523-32.
• [48] 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.
• [49] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [50] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [51] 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.
• [52] 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.
• [53] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [54] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [55] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [56] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.