Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFQOT3C)

• DOT Name: Fermitin family homolog 3 (FERMT3)
• Synonyms: Kindlin-3; MIG2-like protein; Unc-112-related protein 2
• Gene Name: FERMT3
• Related Disease:
  Leukocyte adhesion deficiency 3
  Adult glioblastoma
  Attention deficit hyperactivity disorder
  Autism
  Autosomal dominant osteopetrosis 2
  Breast neoplasm
  Coagulation defect
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Immunodeficiency
  Inherited bleeding disorder, platelet-type
  Leukocyte adhesion deficiency type 1
  Myocardial infarction
  Osteopetrosis
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Small lymphocytic lymphoma
  Bacterial infection
  Advanced cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Glanzmann thrombasthenia
  Leiomyoma
  Leiomyosarcoma
  Melanoma
  Neoplasm
  Osteosarcoma
  Uterine fibroids
• UniProt ID: URP2_HUMAN
• PDB ID: 2YS3; 6V97; 6V9G; 7C3M
• Pfam ID: PF00373 ; PF18124 ; PF00169
• Sequence:
  MAGMKTASGDYIDSSWELRVFVGEEDPEAESVTLRVTGESHIGGVLLKIVEQINRKQDWS
  DHAIWWEQKRQWLLQTHWTLDKYGILADARLFFGPQHRPVILRLPNRRALRLRASFSQPL
  FQAVAAICRLLSIRHPEELSLLRAPEKKEKKKKEKEPEEELYDLSKVVLAGGVAPALFRG
  MPAHFSDSAQTEACYHMLSRPQPPPDPLLLQRLPRPSSLSDKTQLHSRWLDSSRCLMQQG
  IKAGDALWLRFKYYSFFDLDPKTDPVRLTQLYEQARWDLLLEEIDCTEEEMMVFAALQYH
  INKLSQSGEVGEPAGTDPGLDDLDVALSNLEVKLEGSAPTDVLDSLTTIPELKDHLRIFR
  IPRRPRKLTLKGYRQHWVVFKETTLSYYKSQDEAPGDPIQQLNLKGCEVVPDVNVSGQKF
  CIKLLVPSPEGMSEIYLRCQDEQQYARWMAGCRLASKGRTMADSSYTSEVQAILAFLSLQ
  RTGSGGPGNHPHGPDASAEGLNPYGLVAPRFQRKFKAKQLTPRILEAHQNVAQLSLAEAQ
  LRFIQAWQSLPDFGISYVMVRFKGSRKDEILGIANNRLIRIDLAVGDVVKTWRFSNMRQW
  NVNWDIRQVAIEFDEHINVAFSCVSASCRIVHEYIGGYIFLSTRERARGEELDEDLFLQL
  TGGHEAF
• Function: Plays a central role in cell adhesion in hematopoietic cells. Acts by activating the integrin beta-1-3 (ITGB1, ITGB2 and ITGB3). Required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells. Required for activation of integrin beta-2 (ITGB2) in polymorphonuclear granulocytes (PMNs); Isoform 2 may act as a repressor of NF-kappa-B and apoptosis.
• Tissue Specificity: Highly expressed in lymph node. Expressed in thymus, spleen and leukocytes. Weakly expressed in placenta, small intestine, stomach, testis and lung. Overexpressed in B-cell malignancies.
• KEGG Pathway: Platelet activation (hsa04611)
• Reactome Pathway: Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Leukocyte adhesion deficiency 3	DISTEN13	Definitive	Autosomal recessive	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Genetic Variation	[3]
Autism	DISV4V1Z	Strong	Biomarker	[4]
Autosomal dominant osteopetrosis 2	DISC8H8S	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Coagulation defect	DIS9X3H6	Strong	Genetic Variation	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Immunodeficiency	DIS093I0	Strong	Genetic Variation	[9]
Inherited bleeding disorder, platelet-type	DISIUNXT	Strong	Biomarker	[5]
Leukocyte adhesion deficiency type 1	DISA1J7W	Strong	Genetic Variation	[10]
Myocardial infarction	DIS655KI	Strong	Biomarker	[11]
Osteopetrosis	DIS7GHNM	Strong	Genetic Variation	[12]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[13]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[13]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[14]
Small lymphocytic lymphoma	DIS30POX	Strong	Biomarker	[14]
Bacterial infection	DIS5QJ9S	moderate	Genetic Variation	[15]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[16]
Bone osteosarcoma	DIST1004	Limited	Altered Expression	[17]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[16]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[16]
Glanzmann thrombasthenia	DISFGGTG	Limited	Biomarker	[18]
Leiomyoma	DISLDDFN	Limited	Altered Expression	[19]
Leiomyosarcoma	DIS6COXM	Limited	Genetic Variation	[19]
Melanoma	DIS1RRCY	Limited	Altered Expression	[16]
Neoplasm	DISZKGEW	Limited	Altered Expression	[6]
Osteosarcoma	DISLQ7E2	Limited	Altered Expression	[17]
Uterine fibroids	DISBZRMJ	Limited	Altered Expression	[19]

5 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 Fermitin family homolog 3 (FERMT3).	[20]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Fermitin family homolog 3 (FERMT3).	[24]
Triclosan	DMZUR4N	Approved	Triclosan increases the methylation of Fermitin family homolog 3 (FERMT3).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Fermitin family homolog 3 (FERMT3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Fermitin family homolog 3 (FERMT3).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Fermitin family homolog 3 (FERMT3).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Fermitin family homolog 3 (FERMT3).	[22]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Fermitin family homolog 3 (FERMT3).	[23]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Fermitin family homolog 3 (FERMT3).	[25]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Fermitin family homolog 3 (FERMT3).	[27]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Fermitin family homolog 3 (FERMT3).	[29]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Fermitin family homolog 3 (FERMT3).	[30]

References

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• [2] FERMT3 contributes to glioblastoma cell proliferation and chemoresistance to temozolomide through integrin mediated Wnt signaling.Neurosci Lett. 2017 Sep 14;657:77-83. doi: 10.1016/j.neulet.2017.07.057. Epub 2017 Aug 1.
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• [4] iTRAQ-Based Proteomic Analysis Reveals Protein Profile in Plasma from Children with Autism.Proteomics Clin Appl. 2018 May;12(3):e1700085. doi: 10.1002/prca.201700085. Epub 2018 Jan 18.
• [5] Kindlin-3 is essential for integrin activation and platelet aggregation. Nat Med. 2008 Mar;14(3):325-30. doi: 10.1038/nm1722. Epub 2008 Feb 17.
• [6] Distinct expression profiles and functions of Kindlins in breast cancer.J Exp Clin Cancer Res. 2018 Nov 26;37(1):281. doi: 10.1186/s13046-018-0955-4.
• [7] Novel variants in FERMT3 and RASGRP2-Genetic linkage in Glanzmann-like bleeding disorders.Pediatr Blood Cancer. 2020 Feb;67(2):e28078. doi: 10.1002/pbc.28078. Epub 2019 Nov 14.
• [8] Hepatitis B virus X protein related lncRNA WEE2-AS1 promotes hepatocellular carcinoma proliferation and invasion.Biochem Biophys Res Commun. 2019 Jan 1;508(1):79-86. doi: 10.1016/j.bbrc.2018.11.091. Epub 2018 Nov 22.
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• [10] Leucocyte adhesion deficiency-A multicentre national experience.Eur J Clin Invest. 2019 Feb;49(2):e13047. doi: 10.1111/eci.13047. Epub 2019 Jan 4.
• [11] The Integrin Activating Protein Kindlin-3 Is Cleaved in Human Platelets during ST-Elevation Myocardial Infarction.Int J Mol Sci. 2019 Dec 6;20(24):6154. doi: 10.3390/ijms20246154.
• [12] Hematopoietic stem cell transplantation corrects osteopetrosis in a child carrying a novel homozygous mutation in the FERMT3 gene.Bone. 2017 Apr;97:126-129. doi: 10.1016/j.bone.2017.01.012. Epub 2017 Jan 14.
• [13] Discovery of serum biomarkers implicated in the onset and progression of serous ovarian cancer in a rat model using iTRAQ technique.Eur J Obstet Gynecol Reprod Biol. 2012 Nov;165(1):96-103. doi: 10.1016/j.ejogrb.2012.06.031. Epub 2012 Jul 18.
• [14] In vivo adhesion of malignant B cells to bone marrow microvasculature is regulated by 41 cytoplasmic-binding proteins.Leukemia. 2016 Apr;30(4):861-72. doi: 10.1038/leu.2015.332. Epub 2015 Dec 10.
• [15] Optimal T Cell Activation and B Cell Antibody Responses In Vivo Require the Interaction between Leukocyte Function-Associated Antigen-1 and Kindlin-3.J Immunol. 2015 Jul 1;195(1):105-15. doi: 10.4049/jimmunol.1402741. Epub 2015 May 18.
• [16] Expression of kindlin-3 in melanoma cells impedes cell migration and metastasis.Cell Adh Migr. 2017 Sep 3;11(5-6):419-433. doi: 10.1080/19336918.2016.1243645. Epub 2016 Nov 2.
• [17] Prognostic implications of Kindlin proteins in human osteosarcoma.Onco Targets Ther. 2017 Feb 7;10:657-665. doi: 10.2147/OTT.S125418. eCollection 2017.
• [18] Lessons from rare maladies: leukocyte adhesion deficiency syndromes.Curr Opin Hematol. 2013 Jan;20(1):16-25. doi: 10.1097/MOH.0b013e32835a0091.
• [19] 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.
• [20] 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.
• [21] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [24] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [25] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [26] Pregnancy exposure to synthetic phenols and placental DNA methylation - An epigenome-wide association study in male infants from the EDEN cohort. Environ Pollut. 2021 Dec 1;290:118024. doi: 10.1016/j.envpol.2021.118024. Epub 2021 Aug 21.
• [27] 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.
• [28] 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.
• [29] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.