Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9HSQ8F)

• DOT Name: Plakophilin-1 (PKP1)
• Synonyms: Band 6 protein; B6P
• Gene Name: PKP1
• Related Disease:
  Epidermolysis bullosa simplex due to plakophilin deficiency
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Adenocarcinoma
  Barrett esophagus
  Cardiomyopathy
  Ectodermal dysplasia
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lung squamous cell carcinoma
  Melanoma
  Metastatic melanoma
  Neoplasm
  Palmoplantar keratosis
  Panic disorder
  Squamous cell carcinoma
  Trichohepatoenteric syndrome
  X-linked hypohidrotic ectodermal dysplasia
  Hepatocellular carcinoma
• UniProt ID: PKP1_HUMAN
• PDB ID: 1XM9
• Pfam ID: PF00514
• Sequence:
  MNHSPLKTALAYECFQDQDNSTLALPSDQKMKTGTSGRQRVQEQVMMTVKRQKSKSSQSS
  TLSHSNRGSMYDGLADNYNYGTTSRSSYYSKFQAGNGSWGYPIYNGTLKREPDNRRFSSY
  SQMENWSRHYPRGSCNTTGAGSDICFMQKIKASRSEPDLYCDPRGTLRKGTLGSKGQKTT
  QNRYSFYSTCSGQKAIKKCPVRPPSCASKQDPVYIPPISCNKDLSFGHSRASSKICSEDI
  ECSGLTIPKAVQYLSSQDEKYQAIGAYYIQHTCFQDESAKQQVYQLGGICKLVDLLRSPN
  QNVQQAAAGALRNLVFRSTTNKLETRRQNGIREAVSLLRRTGNAEIQKQLTGLLWNLSST
  DELKEELIADALPVLADRVIIPFSGWCDGNSNMSREVVDPEVFFNATGCLRKRLGMRELL
  ALVPQRATSSRVNLSSADAGRQTMRNYSGLIDSLMAYVQNCVAASRCDDKSVENCMCVLH
  NLSYRLDAEVPTRYRQLEYNARNAYTEKSSTGCFSNKSDKMMNNNYDCPLPEEETNPKGS
  GWLYHSDAIRTYLNLMGKSKKDATLEACAGALQNLTASKGLMSSGMSQLIGLKEKGLPQI
  ARLLQSGNSDVVRSGASLLSNMSRHPLLHRVMGNQVFPEVTRLLTSHTGNTSNSEDILSS
  ACYTVRNLMASQPQLAKQYFSSSMLNNIINLCRSSASPKAAEAARLLLSDMWSSKELQGV
  LRQQGFDRNMLGTLAGANSLRNFTSRF
• Function: Seems to play a role in junctional plaques. Contributes to epidermal morphogenesis. May facilitate the formation of intermediate filaments.
• Tissue Specificity: .Expressed in stratified squamous, complex, glandular duct and bladder epithelia (at protein level).; [Isoform 2]: Widely expressed (at protein level).
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Keratinization (R-HSA-6805567)
  Formation of the cornified envelope (R-HSA-6809371)
  Apoptotic cleavage of cell adhesion proteins (R-HSA-351906)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epidermolysis bullosa simplex due to plakophilin deficiency	DISAIFGB	Definitive	Autosomal recessive	[1]
Prostate cancer	DISF190Y	Definitive	Altered Expression	[2]
Prostate carcinoma	DISMJPLE	Definitive	Altered Expression	[2]
Prostate neoplasm	DISHDKGQ	Definitive	Biomarker	[2]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[3]
Barrett esophagus	DIS416Y7	Strong	Posttranslational Modification	[4]
Cardiomyopathy	DISUPZRG	Strong	Altered Expression	[5]
Ectodermal dysplasia	DISLRS4M	Strong	Genetic Variation	[6]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[4]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Altered Expression	[7]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[7]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[7]
Lung squamous cell carcinoma	DISXPIBD	Strong	Biomarker	[8]
Melanoma	DIS1RRCY	Strong	Altered Expression	[9]
Metastatic melanoma	DISSL43L	Strong	Altered Expression	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[9]
Palmoplantar keratosis	DISYQGFB	Strong	Altered Expression	[6]
Panic disorder	DISD3VNY	Strong	Genetic Variation	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[3]
Trichohepatoenteric syndrome	DISL3ODF	Strong	Genetic Variation	[11]
X-linked hypohidrotic ectodermal dysplasia	DISST0XM	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Limited	Biomarker	[13]

1 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 Plakophilin-1 (PKP1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Plakophilin-1 (PKP1).	[15]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Plakophilin-1 (PKP1).	[16]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Plakophilin-1 (PKP1).	[17]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Plakophilin-1 (PKP1).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Plakophilin-1 (PKP1).	[19]

References

• [1] Ectodermal dysplasia-skin fragility syndrome due to a new homozygous internal deletion mutation in the PKP1 gene. Australas J Dermatol. 2012 Feb;53(1):61-5. doi: 10.1111/j.1440-0960.2011.00846.x. Epub 2011 Dec 29.
• [2] Plakophilin 1-deficient cells upregulate SPOCK1: implications for prostate cancer progression.Tumour Biol. 2015 Dec;36(12):9567-77. doi: 10.1007/s13277-015-3628-3. Epub 2015 Jul 4.
• [3] The value of desmosomal plaque-related markers to distinguish squamous cell carcinoma and adenocarcinoma of the lung.Ups J Med Sci. 2020 Feb;125(1):19-29. doi: 10.1080/03009734.2019.1692101. Epub 2019 Dec 6.
• [4] Aberrantly methylated PKP1 in the progression of Barrett's esophagus to esophageal adenocarcinoma.Genes Chromosomes Cancer. 2012 Apr;51(4):384-93. doi: 10.1002/gcc.21923. Epub 2011 Dec 14.
• [5] Novel truncating mutations in PKP1 and DSP cause similar skin phenotypes in two Brazilian families.Br J Dermatol. 2009 Mar;160(3):692-7. doi: 10.1111/j.1365-2133.2008.08900.x. Epub 2008 Oct 21.
• [6] Ectodermal dysplasia-skin fragility syndrome. Dermatol Clin. 2010 Jan;28(1):125-9. doi: 10.1016/j.det.2009.10.014.
• [7] Plakophilin 1 is methylated and has a tumor suppressive activity in human lung cancer.Exp Mol Pathol. 2019 Jun;108:73-79. doi: 10.1016/j.yexmp.2019.04.001. Epub 2019 Apr 1.
• [8] Plakophilin 1 enhances MYC translation, promoting squamous cell lung cancer.Oncogene. 2020 Aug;39(32):5479-5493. doi: 10.1038/s41388-019-1129-3. Epub 2019 Dec 10.
• [9] Coexpression network analysis identified that plakophilin 1 is associated with the metastasis in human melanoma.Biomed Pharmacother. 2019 Mar;111:1234-1242. doi: 10.1016/j.biopha.2018.12.135. Epub 2019 Jan 15.
• [10] Genome-wide association study of panic disorder in the Japanese population.J Hum Genet. 2009 Feb;54(2):122-6. doi: 10.1038/jhg.2008.17. Epub 2009 Jan 23.
• [11] Compound heterozygosity for new splice site mutations in the plakophilin 1 gene (PKP1) in a Chinese case of ectodermal dysplasia-skin fragility syndrome.Acta Derm Venereol. 2005;85(5):394-9. doi: 10.1080/00015550510037684.
• [12] Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin 1.Br J Dermatol. 1999 Feb;140(2):297-307. doi: 10.1046/j.1365-2133.1999.02667.x.
• [13] Hepatocellular carcinoma-associated protein markers investigated by MALDI-TOF MS.Mol Med Rep. 2010 Jul-Aug;3(4):589-96. doi: 10.3892/mmr_00000302.
• [14] 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.
• [15] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [18] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [19] Comparative mechanisms of PAH toxicity by benzo[a]pyrene and dibenzo[def,p]chrysene in primary human bronchial epithelial cells cultured at air-liquid interface. Toxicol Appl Pharmacol. 2019 Sep 15;379:114644.