Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTG2EZEN)

• DOT Name: Keratin, type II cytoskeletal 2 epidermal (KRT2)
• Synonyms: Cytokeratin-2e; CK-2e; Epithelial keratin-2e; Keratin-2 epidermis; Keratin-2e; K2e; Type-II keratin Kb2
• Gene Name: KRT2
• Related Disease:
  Superficial epidermolytic ichthyosis
  Congenital reticular ichthyosiform erythroderma
  Exfoliative ichthyosis
  Breast cancer
  Breast carcinoma
  Contact dermatitis
  Epidermolytic ichthyosis
• UniProt ID: K22E_HUMAN
• Pfam ID: PF00038 ; PF16208
• Sequence:
  MSCQISCKSRGRGGGGGGFRGFSSGSAVVSGGSRRSTSSFSCLSRHGGGGGGFGGGGFGS
  RSLVGLGGTKSISISVAGGGGGFGAAGGFGGRGGGFGGGSSFGGGSGFSGGGFGGGGFGG
  GRFGGFGGPGGVGGLGGPGGFGPGGYPGGIHEVSVNQSLLQPLNVKVDPEIQNVKAQERE
  QIKTLNNKFASFIDKVRFLEQQNQVLQTKWELLQQMNVGTRPINLEPIFQGYIDSLKRYL
  DGLTAERTSQNSELNNMQDLVEDYKKKYEDEINKRTAAENDFVTLKKDVDNAYMIKVELQ
  SKVDLLNQEIEFLKVLYDAEISQIHQSVTDTNVILSMDNSRNLDLDSIIAEVKAQYEEIA
  QRSKEEAEALYHSKYEELQVTVGRHGDSLKEIKIEISELNRVIQRLQGEIAHVKKQCKNV
  QDAIADAEQRGEHALKDARNKLNDLEEALQQAKEDLARLLRDYQELMNVKLALDVEIATY
  RKLLEGEECRMSGDLSSNVTVSVTSSTISSNVASKAAFGGSGGRGSSSGGGYSSGSSSYG
  SGGRQSGSRGGSGGGGSISGGGYGSGGGSGGRYGSGGGSKGGSISGGGYGSGGGKHSSGG
  GSRGGSSSGGGYGSGGGGSSSVKGSSGEAFGSSVTFSFR
• Function: Probably contributes to terminal cornification. Associated with keratinocyte activation, proliferation and keratinization. Required for maintenance of corneocytes and keratin filaments in suprabasal keratinocytes in the epidermis of the ear, potentially via moderation of expression and localization of keratins and their partner proteins. Plays a role in the establishment of the epidermal barrier on plantar skin.
• Tissue Specificity: Expressed in the upper spinous and granular suprabasal layers of normal adult epidermal tissues from most body sites including thigh, breast nipple, foot sole, penile shaft and axilla. Not present in foreskin, squamous metaplasias and carcinomas. Expression in hypertrophic and keloid scars begins in the deepest suprabasal layer. Weakly expressed in normal gingiva and tongue, however expression is induced in benign keratoses of lingual mucosa and in mild-to-moderate oral dysplasia with orthokeratinization.
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Superficial epidermolytic ichthyosis	DISWX6O4	Definitive	Autosomal dominant	[1]
Congenital reticular ichthyosiform erythroderma	DISYAB1Q	Strong	Genetic Variation	[2]
Exfoliative ichthyosis	DISH776B	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[4]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[4]
Contact dermatitis	DISQ3AU0	Limited	Biomarker	[5]
Epidermolytic ichthyosis	DISJPEP3	Limited	Genetic Variation	[2]

8 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 Keratin, type II cytoskeletal 2 epidermal (KRT2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[9]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[10]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[11]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[6]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Keratin, type II cytoskeletal 2 epidermal (KRT2).	[13]

References

• [1] Mutations in the rod domain of keratin 2e in patients with ichthyosis bullosa of Siemens. Nat Genet. 1994 Aug;7(4):485-90. doi: 10.1038/ng0894-485.
• [2] Expanding the Clinical and Genetic Spectrum of KRT1, KRT2 and KRT10 Mutations in Keratinopathic Ichthyosis. Acta Derm Venereol. 2016 May;96(4):473-8. doi: 10.2340/00015555-2299.
• [3] Genetic linkage of the keratin type II gene cluster with ichthyosis bullosa of Siemens and with autosomal dominant ichthyosis exfoliativa.J Invest Dermatol. 1994 Sep;103(3):282-5. doi: 10.1111/1523-1747.ep12394335.
• [4] Changes in keratin expression during metastatic progression of breast cancer: impact on the detection of circulating tumor cells.Clin Cancer Res. 2012 Feb 15;18(4):993-1003. doi: 10.1158/1078-0432.CCR-11-2100. Epub 2012 Jan 6.
• [5] Genes specifically modulated in sensitized skins allow the detection of sensitizers in a reconstructed human skin modelDevelopment of the SENS-IS assay. Toxicol In Vitro. 2015 Jun;29(4):787-802.
• [6] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [7] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [8] 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.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [11] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [12] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [13] 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.