Details of Drug Off-Target (DOT)

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

• DOT Name: Fermitin family homolog 2 (FERMT2)
• Synonyms: Kindlin-2; Mitogen-inducible gene 2 protein; MIG-2; Pleckstrin homology domain-containing family C member 1; PH domain-containing family C member 1
• Gene Name: FERMT2
• Related Disease:
  Advanced cancer
  Invasive breast carcinoma
  Matthew-Wood syndrome
  Nephropathy
  Alzheimer disease
  Amyloidosis
  Angle-closure glaucoma
  Bladder cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Cardiac failure
  Clear cell renal carcinoma
  Colorectal carcinoma
  Congestive heart failure
  Esophageal cancer
  Gastric cancer
  Glioma
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
  Kidney failure
  Lipodystrophy
  Lung adenocarcinoma
  MASS syndrome
  Neoplasm
  Neoplasm of esophagus
  Obesity
  Osteosarcoma
  Pancreatic cancer
  Pancreatic ductal carcinoma
  Prostate cancer
  Prostate carcinoma
  Renal cell carcinoma
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Choriocarcinoma
  Primary angle-closure glaucoma
  Chondrosarcoma
  Cutaneous melanoma
  Epithelial ovarian cancer
  Esophageal squamous cell carcinoma
  Leiomyoma
  Leiomyosarcoma
  Melanoma
  Renal fibrosis
  Uterine fibroids
• UniProt ID: FERM2_HUMAN
• PDB ID: 2LGX; 2LKO; 2MSU; 4F7H; 6U4N; 6XTJ
• Pfam ID: PF00373 ; PF18124 ; PF00169
• Sequence:
  MALDGIRMPDGCYADGTWELSVHVTDLNRDVTLRVTGEVHIGGVMLKLVEKLDVKKDWSD
  HALWWEKKRTWLLKTHWTLDKYGIQADAKLQFTPQHKLLRLQLPNMKYVKVKVNFSDRVF
  KAVSDICKTFNIRHPEELSLLKKPRDPTKKKKKKLDDQSEDEALELEGPLITPGSGSIYS
  SPGLYSKTMTPTYDAHDGSPLSPTSAWFGDSALSEGNPGILAVSQPITSPEILAKMFKPQ
  ALLDKAKINQGWLDSSRSLMEQDVKENEALLLRFKYYSFFDLNPKYDAIRINQLYEQAKW
  AILLEEIECTEEEMMMFAALQYHINKLSIMTSENHLNNSDKEVDEVDAALSDLEITLEGG
  KTSTILGDITSIPELADYIKVFKPKKLTLKGYKQYWCTFKDTSISCYKSKEESSGTPAHQ
  MNLRGCEVTPDVNISGQKFNIKLLIPVAEGMNEIWLRCDNEKQYAHWMAACRLASKGKTM
  ADSSYNLEVQNILSFLKMQHLNPDPQLIPEQITTDITPECLVSPRYLKKYKNKQITARIL
  EAHQNVAQMSLIEAKMRFIQAWQSLPEFGITHFIARFQGGKKEELIGIAYNRLIRMDAST
  GDAIKTWRFSNMKQWNVNWEIKMVTVEFADEVRLSFICTEVDCKVVHEFIGGYIFLSTRA
  KDQNESLDEEMFYKLTSGWV
• Function: Scaffolding protein that enhances integrin activation mediated by TLN1 and/or TLN2, but activates integrins only weakly by itself. Binds to membranes enriched in phosphoinositides. Enhances integrin-mediated cell adhesion onto the extracellular matrix and cell spreading; this requires both its ability to interact with integrins and with phospholipid membranes. Required for the assembly of focal adhesions. Participates in the connection between extracellular matrix adhesion sites and the actin cytoskeleton and also in the orchestration of actin assembly and cell shape modulation. Recruits FBLIM1 to focal adhesions. Plays a role in the TGFB1 and integrin signaling pathways. Stabilizes active CTNNB1 and plays a role in the regulation of transcription mediated by CTNNB1 and TCF7L2/TCF4 and in Wnt signaling.
• Tissue Specificity: Ubiquitous. Found in numerous tumor tissues.
• Reactome Pathway:
  RAC1 GTPase cycle (R-HSA-9013149)
  RAC3 GTPase cycle (R-HSA-9013423)
  Cell-extracellular matrix interactions (R-HSA-446353)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Invasive breast carcinoma	DISANYTW	Definitive	Biomarker	[2]
Matthew-Wood syndrome	DISA7HR7	Definitive	Altered Expression	[3]
Nephropathy	DISXWP4P	Definitive	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Amyloidosis	DISHTAI2	Strong	Genetic Variation	[6]
Angle-closure glaucoma	DISZ95KY	Strong	Genetic Variation	[7]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[8]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[8]
Breast cancer	DIS7DPX1	Strong	Biomarker	[9]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[9]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[10]
Cardiac failure	DISDC067	Strong	Biomarker	[11]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[12]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[11]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[10]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[11]
Kidney failure	DISOVQ9P	Strong	Altered Expression	[13]
Lipodystrophy	DIS3SGVD	Strong	Altered Expression	[14]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[15]
MASS syndrome	DISI3721	Strong	Biomarker	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[15]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[10]
Obesity	DIS47Y1K	Strong	Genetic Variation	[16]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[8]
Pancreatic cancer	DISJC981	Strong	Biomarker	[3]
Pancreatic ductal carcinoma	DIS26F9Q	Strong	Altered Expression	[8]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[17]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[18]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[19]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[8]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[8]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[8]
Choriocarcinoma	DISDBVNL	moderate	Altered Expression	[20]
Primary angle-closure glaucoma	DISX8UKZ	moderate	Genetic Variation	[7]
Chondrosarcoma	DIS4I7JB	Limited	Altered Expression	[8]
Cutaneous melanoma	DIS3MMH9	Limited	Biomarker	[21]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[22]
Esophageal squamous cell carcinoma	DIS5N2GV	Limited	Biomarker	[23]
Leiomyoma	DISLDDFN	Limited	Altered Expression	[24]
Leiomyosarcoma	DIS6COXM	Limited	Genetic Variation	[24]
Melanoma	DIS1RRCY	Limited	Biomarker	[25]
Renal fibrosis	DISMHI3I	Limited	Biomarker	[26]
Uterine fibroids	DISBZRMJ	Limited	Altered Expression	[24]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Fermitin family homolog 2 (FERMT2) affects the response to substance of Fluorouracil.	[47]
Topotecan	DMP6G8T	Approved	Fermitin family homolog 2 (FERMT2) affects the response to substance of Topotecan.	[47]

19 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 Fermitin family homolog 2 (FERMT2).	[27]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Fermitin family homolog 2 (FERMT2).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fermitin family homolog 2 (FERMT2).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fermitin family homolog 2 (FERMT2).	[30]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Fermitin family homolog 2 (FERMT2).	[31]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fermitin family homolog 2 (FERMT2).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Fermitin family homolog 2 (FERMT2).	[33]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Fermitin family homolog 2 (FERMT2).	[34]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Fermitin family homolog 2 (FERMT2).	[35]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Fermitin family homolog 2 (FERMT2).	[36]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Fermitin family homolog 2 (FERMT2).	[37]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Fermitin family homolog 2 (FERMT2).	[38]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Fermitin family homolog 2 (FERMT2).	[39]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Fermitin family homolog 2 (FERMT2).	[40]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Fermitin family homolog 2 (FERMT2).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fermitin family homolog 2 (FERMT2).	[43]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Fermitin family homolog 2 (FERMT2).	[44]
chloropicrin	DMSGBQA	Investigative	chloropicrin increases the expression of Fermitin family homolog 2 (FERMT2).	[45]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Fermitin family homolog 2 (FERMT2).	[46]

2 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 affects the phosphorylation of Fermitin family homolog 2 (FERMT2).	[42]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Fermitin family homolog 2 (FERMT2).	[42]

References

• [1] Kindlin-2 promotes hepatocellular carcinoma invasion and metastasis by increasing Wnt/-catenin signaling.J Exp Clin Cancer Res. 2017 Sep 29;36(1):134. doi: 10.1186/s13046-017-0603-4.
• [2] Kindlin-2 could influence breast nodule elasticity and improve lymph node metastasis in invasive breast cancer.Sci Rep. 2017 Jul 28;7(1):6753. doi: 10.1038/s41598-017-07075-1.
• [3] Kindlin-2 in pancreatic stellate cells promotes the progression of pancreatic cancer.Cancer Lett. 2017 Apr 1;390:103-114. doi: 10.1016/j.canlet.2017.01.008. Epub 2017 Jan 16.
• [4] Kindlin-2 mediates activation of TGF-/Smad signaling and renal fibrosis.J Am Soc Nephrol. 2013 Sep;24(9):1387-98. doi: 10.1681/ASN.2012101041. Epub 2013 May 30.
• [5] Candidate-based screening via gene modulation in human neurons and astrocytes implicates FERMT2 in A and TAU proteostasis.Hum Mol Genet. 2019 Mar 1;28(5):718-735. doi: 10.1093/hmg/ddy376.
• [6] Associations of the Top 20 Alzheimer Disease Risk Variants With Brain Amyloidosis.JAMA Neurol. 2018 Mar 1;75(3):328-341. doi: 10.1001/jamaneurol.2017.4198.
• [7] Integration of Genetic and Biometric Risk Factors for Detection of Primary Angle Closure Glaucoma.Am J Ophthalmol. 2019 Dec;208:160-165. doi: 10.1016/j.ajo.2019.07.022. Epub 2019 Aug 1.
• [8] Prognostic value of Kindlin-2 expression in patients with solid tumors: a meta-analysis.Cancer Cell Int. 2018 Oct 22;18:166. doi: 10.1186/s12935-018-0651-7. eCollection 2018.
• [9] Integrin-interacting protein Kindlin-2 induces mammary tumors in transgenic mice.Sci China Life Sci. 2019 Feb;62(2):225-234. doi: 10.1007/s11427-018-9336-6. Epub 2018 Nov 19.
• [10] Differential expression of Kindlin-1 and Kindlin-2 correlates with esophageal cancer progression and epidemiology.Sci China Life Sci. 2017 Nov;60(11):1214-1222. doi: 10.1007/s11427-016-9044-5. Epub 2017 Jun 29.
• [11] Kindlin-2 suppresses transcription factor GATA4 through interaction with SUV39H1 to attenuate hypertrophy.Cell Death Dis. 2019 Nov 26;10(12):890. doi: 10.1038/s41419-019-2121-0.
• [12] Kindlin-2 inhibited the growth and migration of colorectal cancer cells.Tumour Biol. 2015 Jun;36(6):4107-14. doi: 10.1007/s13277-015-3044-8. Epub 2015 Jan 30.
• [13] Kindlin-2 Association with Rho GDP-Dissociation Inhibitor Suppresses Rac1 Activation and Podocyte Injury.J Am Soc Nephrol. 2017 Dec;28(12):3545-3562. doi: 10.1681/ASN.2016091021. Epub 2017 Aug 3.
• [14] Lipoatrophy and metabolic disturbance in mice with adipose-specific deletion of kindlin-2.JCI Insight. 2019 Jul 11;4(13):e128405. doi: 10.1172/jci.insight.128405. eCollection 2019 Jul 11.
• [15] Kindlin-2 links mechano-environment to proline synthesis and tumor growth.Nat Commun. 2019 Feb 19;10(1):845. doi: 10.1038/s41467-019-08772-3.
• [16] Genetic variation at the CELF1 (CUGBP, elav-like family member 1 gene) locus is genome-wide associated with Alzheimer's disease and obesity.Am J Med Genet B Neuropsychiatr Genet. 2014 Jun;165B(4):283-93. doi: 10.1002/ajmg.b.32234. Epub 2014 May 1.
• [17] Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.Nat Genet. 2013 Apr;45(4):385-91, 391e1-2. doi: 10.1038/ng.2560.
• [18] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [19] Kindlin? promotes clear cell renal cell carcinoma progression through the Wnt signaling pathway.Oncol Rep. 2017 Sep;38(3):1551-1560. doi: 10.3892/or.2017.5789. Epub 2017 Jul 4.
• [20] Lysis Buffer Choices Are Key Considerations to Ensure Effective Sample Solubilization for Protein Electrophoresis.Methods Mol Biol. 2019;1855:61-72. doi: 10.1007/978-1-4939-8793-1_5.
• [21] Elevated kindlin-2 promotes tumour progression and angiogenesis through the mTOR/VEGFA pathway in melanoma.Aging (Albany NY). 2019 Aug 19;11(16):6273-6285. doi: 10.18632/aging.102187. Epub 2019 Aug 19.
• [22] Kindlin-2 inhibits serous epithelial ovarian cancer peritoneal dissemination and predicts patient outcomes.Biochem Biophys Res Commun. 2014 Mar 28;446(1):187-94. doi: 10.1016/j.bbrc.2014.02.087. Epub 2014 Feb 27.
• [23] miR-338-5p inhibits cell proliferation, colony formation, migration and cisplatin resistance in esophageal squamous cancer cells by targeting FERMT2.Carcinogenesis. 2019 Jul 20;40(7):883-892. doi: 10.1093/carcin/bgy189.
• [24] Expression of the mitogen-inducible gene-2 (mig-2) is elevated in human uterine leiomyomas but not in leiomyosarcomas.Hum Pathol. 2004 Jan;35(1):55-60. doi: 10.1016/j.humpath.2003.08.019.
• [25] p62/SQSTM1 Fuels Melanoma Progression by Opposing mRNA Decay of a Selective Set of Pro-metastatic Factors.Cancer Cell. 2019 Jan 14;35(1):46-63.e10. doi: 10.1016/j.ccell.2018.11.008. Epub 2018 Dec 20.
• [26] Kindlin-2 Inhibits the Hippo Signaling Pathway by Promoting Degradation of MOB1.Cell Rep. 2019 Dec 10;29(11):3664-3677.e5. doi: 10.1016/j.celrep.2019.11.035.
• [27] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [28] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] 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.
• [31] 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.
• [32] 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.
• [33] Gene expression profile induced by arsenic trioxide in chronic lymphocytic leukemia cells reveals a central role for heme oxygenase-1 in apoptosis and regulation of matrix metalloproteinase-9. Oncotarget. 2016 Dec 13;7(50):83359-83377.
• [34] Gene microarray analysis of human renal cell carcinoma: the effects of HDAC inhibition and retinoid treatment. Cancer Biol Ther. 2008 Oct;7(10):1607-18.
• [35] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [36] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [37] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [38] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [39] 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.
• [40] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [41] 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.
• [42] 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.
• [43] 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.
• [44] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [45] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [46] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.
• [47] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.