Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8875JE)

• DOT Name: Raftlin (RFTN1)
• Synonyms: Cell migration-inducing gene 2 protein; Raft-linking protein
• Gene Name: RFTN1
• Related Disease:
  Breast cancer
  Breast carcinoma
  Leiomyoma
  Leiomyosarcoma
  Uterine fibroids
• UniProt ID: RFTN1_HUMAN
• Pfam ID: PF15250
• Sequence:
  MGCGLNKLEKRDEKRPGNIYSTLKRPQVETKIDVSYEYRFLEFTTLSAAELPGSSAVRLA
  SLRDLPAQLLELYQQGFSLAALHPFVQPTHEREKTPLEHIFRAILIKKTDRSQKTDLHNE
  GYILELDCCSSLDHPTDQKLIPEFIKKIQEAASQGLKFVGVIPQYHSSVNSAGSSAPVST
  ANSTEDARDAKNARGDHASLENEKPGTGDVCSAPAGRNQSPEPSSGPRGEVPLAKQPSSP
  SGEGDGGELSPQGVSKTLDGPESNPLEVHEEPLSGKMEIFTLFNKPKSHQKCRQYYPVTI
  PLHVSKNGQTVSGLDANWLEHMSDHFRKGGMLVNAVFYLGIVNDSLHGLTDGVFIFEAVS
  TEDSKTIQGYDAIVVEQWTVLEGVEVQTDYVPLLNSLAAYGWQLTCVLPTPVVKTTSEGS
  VSTKQIVFLQRPCLPQKIKKKESKFQWRFSREEMHNRQMRKSKGKLSARDKQQAEENEKN
  LEDQSSKAGDMGNCVSGQQQEGGVSEEMKGPVQEDKGEQLSPGGLLCGVGVEGEAVQNGP
  ASHSRALVGICTGHSNPGEDARDGDAEEVRELGTVEEN
• Function: Involved in protein trafficking via association with clathrin and AP2 complex. Upon bacterial lipopolysaccharide stimulation, mediates internalization of TLR4 to endosomes in dendritic cells and macrophages; and internalization of poly(I:C) to TLR3-positive endosomes in myeloid dendritic cells and epithelial cells; resulting in activation of TICAM1-mediated signaling and subsequent IFNB1 production. Involved in T-cell antigen receptor-mediated signaling by regulating tyrosine kinase LCK localization, T-cell dependent antibody production and cytokine secretion. May regulate B-cell antigen receptor-mediated signaling. May play a pivotal role in the formation and/or maintenance of lipid rafts.
• Tissue Specificity: Expressed in B-cells (at protein level) . Expressed in dendritic cells and macrophages .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	moderate	Altered Expression	[1]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[1]
Leiomyoma	DISLDDFN	Limited	Altered Expression	[2]
Leiomyosarcoma	DIS6COXM	Limited	Genetic Variation	[2]
Uterine fibroids	DISBZRMJ	Limited	Altered Expression	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Raftlin (RFTN1) affects the response to substance of Doxorubicin.	[26]
Topotecan	DMP6G8T	Approved	Raftlin (RFTN1) affects the response to substance of Topotecan.	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Raftlin (RFTN1).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Raftlin (RFTN1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Raftlin (RFTN1).	[23]

22 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 Raftlin (RFTN1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Raftlin (RFTN1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Raftlin (RFTN1).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Raftlin (RFTN1).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Raftlin (RFTN1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Raftlin (RFTN1).	[9]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Raftlin (RFTN1).	[10]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Raftlin (RFTN1).	[11]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Raftlin (RFTN1).	[12]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Raftlin (RFTN1).	[13]
Selenium	DM25CGV	Approved	Selenium increases the expression of Raftlin (RFTN1).	[14]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Raftlin (RFTN1).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Raftlin (RFTN1).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Raftlin (RFTN1).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Raftlin (RFTN1).	[18]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Raftlin (RFTN1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Raftlin (RFTN1).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Raftlin (RFTN1).	[21]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Raftlin (RFTN1).	[22]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Raftlin (RFTN1).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Raftlin (RFTN1).	[15]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Raftlin (RFTN1).	[25]

References

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• [3] 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.
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• [5] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
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• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
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• [12] 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.
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• [14] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
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• [16] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
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• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] 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.
• [22] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [23] 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.
• [24] 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.
• [25] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [26] 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.