Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJOVF68)

• DOT Name: Plakophilin-2 (PKP2)
• Gene Name: PKP2
• Related Disease:
  Arrhythmogenic right ventricular cardiomyopathy
  Arrhythmogenic right ventricular dysplasia 9
  Autism
  Adenocarcinoma
  Atopic dermatitis
  Atrial fibrillation
  Bladder cancer
  Cardiac disease
  Cardiac failure
  Cardiomyopathy
  Colon cancer
  Colon carcinoma
  Congestive heart failure
  Coronary atherosclerosis
  Coronary heart disease
  Dilated cardiomyopathy 1A
  Glioma
  Influenza
  Naxos disease
  Non-small-cell lung cancer
  Paroxysmal familial ventricular fibrillation
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Left ventricular noncompaction
  Brugada syndrome 1
  Catecholaminergic polymorphic ventricular tachycardia
  Conduction system disorder
  Dilated cardiomyopathy
  Sinoatrial node disorder
  Ventricular tachycardia
  Advanced cancer
  Arrhythmia
  Brugada syndrome
  Carcinoma
  Familial atrial fibrillation
  Neoplasm
• UniProt ID: PKP2_HUMAN
• PDB ID: 3TT9
• Pfam ID: PF00514
• Sequence:
  MAAPGAPAEYGYIRTVLGQQILGQLDSSSLALPSEAKLKLAGSSGRGGQTVKSLRIQEQV
  QQTLARKGRSSVGNGNLHRTSSVPEYVYNLHLVENDFVGGRSPVPKTYDMLKAGTTATYE
  GRWGRGTAQYSSQKSVEERSLRHPLRRLEISPDSSPERAHYTHSDYQYSQRSQAGHTLHH
  QESRRAALLVPPRYARSEIVGVSRAGTTSRQRHFDTYHRQYQHGSVSDTVFDSIPANPAL
  LTYPRPGTSRSMGNLLEKENYLTAGLTVGQVRPLVPLQPVTQNRASRSSWHQSSFHSTRT
  LREAGPSVAVDSSGRRAHLTVGQAAAGGSGNLLTERSTFTDSQLGNADMEMTLERAVSML
  EADHMLPSRISAAATFIQHECFQKSEARKRVNQLRGILKLLQLLKVQNEDVQRAVCGALR
  NLVFEDNDNKLEVAELNGVPRLLQVLKQTRDLETKKQITDHTVNLRSRNGWPGAVAHACN
  PSTLGGQGGRITRSGVRDQPDQHGLLWNLSSNDKLKNLMITEALLTLTENIIIPFSGWPE
  GDYPKANGLLDFDIFYNVTGCLRNMSSAGADGRKAMRRCDGLIDSLVHYVRGTIADYQPD
  DKATENCVCILHNLSYQLEAELPEKYSQNIYIQNRNIQTDNNKSIGCFGSRSRKVKEQYQ
  DVPMPEEKSNPKGVEWLWHSIVIRMYLSLIAKSVRNYTQEASLGALQNLTAGSGPMPTSV
  AQTVVQKESGLQHTRKMLHVGDPSVKKTAISLLRNLSRNLSLQNEIAKETLPDLVSIIPD
  TVPSTDLLIETTASACYTLNNIIQNSYQNARDLLNTGGIQKIMAISAGDAYASNKASKAA
  SVLLYSLWAHTELHHAYKKAQFKKTDFVNSRTAKAYHSLKD
• Function: Regulates focal adhesion turnover resulting in changes in focal adhesion size, cell adhesion and cell spreading, potentially via transcriptional modulation of beta-integrins. Required to maintain gingival epithelial barrier function. Required for cardiac sodium current propagation and electrical synchrony in cardiac myocytes, via ANK3 stabilization and modulation of SCN5A/Nav1.5 localization to cell-cell junctions. Required for the formation of desmosome cell junctions in cardiomyocytes, thereby required for the correct formation of the heart, specifically trabeculation and formation of the atria walls. Loss of desmosome cell junctions leads to mis-localization of DSP and DSG2 resulting in disruption of cell-cell adhesion and disordered intermediate filaments. Modulates profibrotic gene expression in cardiomyocytes via regulation of DSP expression and subsequent activation of downstream TGFB1 and MAPK14/p38 MAPK signaling. Required for mitochondrial function, nuclear envelope integrity and positive regulation of SIRT3 transcription via maintaining DES localization at its nuclear envelope and cell tip anchoring points, and thereby preserving regulation of the transcriptional program. Maintenance of nuclear envelope integrity protects against DNA damage and transcriptional dysregulation of genes, especially those involved in the electron transport chain, thereby preserving mitochondrial function and protecting against superoxide radical anion generation. May play a role in junctional plaques. Involved in the inhibition of viral infection by influenza A viruses (IAV). Acts as a host restriction factor for IAV viral propagation, potentially via disrupting the interaction of IAV polymerase complex proteins.
• Tissue Specificity: Detected in heart right ventricle (at protein level). Expressed in gingival epithelial, endothelial and fibroblast cells (at protein level) . Faintly expressed in tracheal epithelial cells (at protein level) . Widely expressed. Found at desmosomal plaques in simple and stratified epithelia and in non-epithelial tissues such as myocardium and lymph node follicles. In most stratified epithelia found in the desmosomes of the basal cell layer and seems to be absent from suprabasal strata.; (Microbial infection) Abundantly expressed in tracheal epithelial cells following influenza A virus infection (at protein level).
• KEGG Pathway:
  Cytoskeleton in muscle cells (hsa04820)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arrhythmogenic right ventricular cardiomyopathy	DIS3V2BE	Definitive	Autosomal dominant	[1]
Arrhythmogenic right ventricular dysplasia 9	DISBHWTY	Definitive	Autosomal dominant	[2]
Autism	DISV4V1Z	Definitive	Genetic Variation	[3]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[4]
Atopic dermatitis	DISTCP41	Strong	Genetic Variation	[5]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[6]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[7]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[8]
Cardiac failure	DISDC067	Strong	Genetic Variation	[9]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[9]
Colon cancer	DISVC52G	Strong	Biomarker	[10]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[10]
Congestive heart failure	DIS32MEA	Strong	Genetic Variation	[9]
Coronary atherosclerosis	DISKNDYU	Strong	Biomarker	[11]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[11]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[12]
Glioma	DIS5RPEH	Strong	Altered Expression	[13]
Influenza	DIS3PNU3	Strong	Biomarker	[14]
Naxos disease	DISL5ZUP	Strong	Genetic Variation	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[16]
Paroxysmal familial ventricular fibrillation	DISRM7IX	Strong	Genetic Variation	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[4]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[7]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[7]
Left ventricular noncompaction	DISJ4QEG	Supportive	Autosomal dominant	[18]
Brugada syndrome 1	DISKBA7V	Disputed	Autosomal dominant	[1]
Catecholaminergic polymorphic ventricular tachycardia	DISSAS1A	Disputed	Autosomal dominant	[1]
Conduction system disorder	DISED5HG	Disputed	Biomarker	[19]
Dilated cardiomyopathy	DISX608J	Disputed	Autosomal dominant	[1]
Sinoatrial node disorder	DISYJI6J	Disputed	Biomarker	[19]
Ventricular tachycardia	DISIBXJ3	Disputed	Genetic Variation	[20]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[16]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[21]
Brugada syndrome	DISSGN0E	Limited	Autosomal dominant	[22]
Carcinoma	DISH9F1N	Limited	Biomarker	[4]
Familial atrial fibrillation	DISL4AGF	Limited	Biomarker	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Paclitaxel	DMLB81S	Approved	Plakophilin-2 (PKP2) decreases the response to substance of Paclitaxel.	[44]
Capecitabine	DMTS85L	Approved	Plakophilin-2 (PKP2) increases the response to substance of Capecitabine.	[44]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Plakophilin-2 (PKP2).	[23]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Plakophilin-2 (PKP2).	[24]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Plakophilin-2 (PKP2).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Plakophilin-2 (PKP2).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Plakophilin-2 (PKP2).	[27]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Plakophilin-2 (PKP2).	[28]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Plakophilin-2 (PKP2).	[29]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Plakophilin-2 (PKP2).	[30]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Plakophilin-2 (PKP2).	[31]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Plakophilin-2 (PKP2).	[32]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Plakophilin-2 (PKP2).	[32]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Plakophilin-2 (PKP2).	[33]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Plakophilin-2 (PKP2).	[34]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Plakophilin-2 (PKP2).	[35]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Plakophilin-2 (PKP2).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Plakophilin-2 (PKP2).	[37]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Plakophilin-2 (PKP2).	[39]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Plakophilin-2 (PKP2).	[40]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Plakophilin-2 (PKP2).	[41]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Plakophilin-2 (PKP2).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Plakophilin-2 (PKP2).	[43]

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 Plakophilin-2 (PKP2).	[38]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Plakophilin-2 (PKP2).	[38]

References

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