Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVXJR26)

• DOT Name: Extracellular tyrosine-protein kinase PKDCC (PKDCC)
• Synonyms: EC 2.7.10.2; Protein kinase domain-containing protein, cytoplasmic; Protein kinase-like protein SgK493; Sugen kinase 493; Vertebrate lonesome kinase
• Gene Name: PKDCC
• Related Disease:
  Asthma
  Rhizomelic limb shortening with dysmorphic features
  Schizophrenia
• UniProt ID: PKDCC_HUMAN
• EC Number: 2.7.10.2
• Pfam ID: PF12260
• Sequence:
  MRRRRAAVAAGFCASFLLGSVLNVLFAPGSEPPRPGQSPEPSPAPGPGRRGGRGELARQI
  RARYEEVQRYSRGGPGPGAGRPERRRLMDLAPGGPGLPRPRPPWARPLSDGAPGWPPAPG
  PGSPGPGPRLGCAALRNVSGAQYMGSGYTKAVYRVRLPGGAAVALKAVDFSGHDLGSCVR
  EFGVRRGCYRLAAHKLLKEMVLLERLRHPNVLQLYGYCYQDSEDIPDTLTTITELGAPVE
  MIQLLQTSWEDRFRICLSLGRLLHHLAHSPLGSVTLLDFRPRQFVLVDGELKVTDLDDAR
  VEETPCAGSTDCILEFPARNFTLPCSAQGWCEGMNEKRNLYNAYRFFFTYLLPHSAPPSL
  RPLLDSIVNATGELAWGVDETLAQLEKVLHLYRSGQYLQNSTASSSTEYQCIPDSTIPQE
  DYRCWPSYHHGSCLLSVFNLAEAVDVCESHAQCRAFVVTNQTTWTGRQLVFFKTGWSQVV
  PDPNKTTYVKASG
• Function: Secreted tyrosine-protein kinase that mediates phosphorylation of extracellular proteins and endogenous proteins in the secretory pathway, which is essential for patterning at organogenesis stages. Mediates phosphorylation of MMP1, MMP13, MMP14, MMP19 and ERP29. Probably plays a role in platelets: rapidly and quantitatively secreted from platelets in response to stimulation of platelet degranulation. May also have serine/threonine protein kinase activity. Required for longitudinal bone growth through regulation of chondrocyte differentiation. May be indirectly involved in protein transport from the Golgi apparatus to the plasma membrane.
• Tissue Specificity: Highly expressed in platelets.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Asthma	DISW9QNS	Strong	Genetic Variation	[1]
Rhizomelic limb shortening with dysmorphic features	DISUUBPQ	Strong	Autosomal recessive	[2]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[10]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[12]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[11]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[13]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[14]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[11]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[17]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[18]

2 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 increases the methylation of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Extracellular tyrosine-protein kinase PKDCC (PKDCC).	[16]

References

• [1] Polymorphisms in recent GWA identified asthma genes CA10, SGK493, and CTNNA3 are associated with disease severity and treatment response in childhood asthma.Immunogenetics. 2014 Mar;66(3):143-51. doi: 10.1007/s00251-013-0755-0. Epub 2014 Jan 10.
• [2] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [3] Genetic Variants Within Key Nodes of the Cascade of Antipsychotic Mechanisms: Effects on Antipsychotic Response and Schizophrenia Psychopathology in a Naturalistic Treatment Setting in Two Independent Korean and Italian Samples.Adv Ther. 2017 Jun;34(6):1482-1497. doi: 10.1007/s12325-017-0555-2. Epub 2017 May 16.
• [4] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [9] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [13] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [14] Gene expression profile of colon cancer cell lines treated with SN-38. Chemotherapy. 2010;56(1):17-25. doi: 10.1159/000287353. Epub 2010 Feb 24.
• [15] 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.
• [16] 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.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [18] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.