Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUL75IR)

• DOT Name: Dual serine/threonine and tyrosine protein kinase (DSTYK)
• Synonyms: EC 2.7.12.1; Dusty protein kinase; Dusty PK; RIP-homologous kinase; Receptor-interacting serine/threonine-protein kinase 5; Sugen kinase 496; SgK496
• Gene Name: DSTYK
• Related Disease:
  Congenital anomalies of kidney and urinary tract 1
  Hereditary spastic paraplegia
  Complex hereditary spastic paraplegia
  Hereditary spastic paraplegia 23
  Renal agenesis, unilateral
• UniProt ID: DUSTY_HUMAN
• EC Number: 2.7.12.1
• Pfam ID: PF00069
• Sequence:
  MEGDGVPWGSEPVSGPGPGGGGMIRELCRGFGRYRRYLGRLRQNLRETQKFFRDIKCSHN
  HTCLSSLTGGGGAERGPAGDVAETGLQAGQLSCISFPPKEEKYLQQIVDCLPCILILGQD
  CNVKCQLLNLLLGVQVLPTTKLGSEESCKLRRLRFTYGTQTRVSLALPGQYELVHTLVAH
  QGNWETIPEEDLEVQENNEDAAHVLAELEVTMHHALLQEVDVVVAPCQGLRPTVDVLGDL
  VNDFLPVITYALHKDELSERDEQELQEIRKYFSFPVFFFKVPKLGSEIIDSSTRRMESER
  SPLYRQLIDLGYLSSSHWNCGAPGQDTKAQSMLVEQSEKLRHLSTFSHQVLQTRLVDAAK
  ALNLVHCHCLDIFINQAFDMQRDLQITPKRLEYTRKKENELYESLMNIANRKQEEMKDMI
  VETLNTMKEELLDDATNMEFKDVIVPENGEPVGTREIKCCIRQIQELIISRLNQAVANKL
  ISSVDYLRESFVGTLERCLQSLEKSQDVSVHITSNYLKQILNAAYHVEVTFHSGSSVTRM
  LWEQIKQIIQRITWVSPPAITLEWKRKVAQEAIESLSASKLAKSICSQFRTRLNSSHEAF
  AASLRQLEAGHSGRLEKTEDLWLRVRKDHAPRLARLSLESCSLQDVLLHRKPKLGQELGR
  GQYGVVYLCDNWGGHFPCALKSVVPPDEKHWNDLALEFHYMRSLPKHERLVDLHGSVIDY
  NYGGGSSIAVLLIMERLHRDLYTGLKAGLTLETRLQIALDVVEGIRFLHSQGLVHRDIKL
  KNVLLDKQNRAKITDLGFCKPEAMMSGSIVGTPIHMAPELFTGKYDNSVDVYAFGILFWY
  ICSGSVKLPEAFERCASKDHLWNNVRRGARPERLPVFDEECWQLMEACWDGDPLKRPLLG
  IVQPMLQGIMNRLCKSNSEQPNRGLDDST
• Function: Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation. Involved in the regulation of both caspase-dependent apoptosis and caspase-independent cell death. In the skin, it plays a predominant role in suppressing caspase-dependent apoptosis in response to UV stress in a range of dermal cell types.
• Tissue Specificity: Predominantly expressed in skeletal muscle and testis. Expressed in basolateral and apical membranes of all tubular epithelia. Expressed in thin ascending limb of the loop of Henle and the distal convoluted tubule. Expressed in all layers of transitional ureteric epithelium and in the ureteric smooth-muscle cells. Weakly expressed in heart, brain, placenta, kidney, pancreas, spleen, thymus, prostate, uterus, small intestine, white blood cells, stomach, spinal cord and adrenal gland. Is widely distributed in the CNS. Also detected in several tumor cell lines. Expressed in the skin .

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Congenital anomalies of kidney and urinary tract 1	DIS2M6PD	Definitive	Autosomal dominant	[1]
Hereditary spastic paraplegia	DISGZQV1	Strong	Genetic Variation	[2]
Complex hereditary spastic paraplegia	DIS9KXQY	Moderate	Autosomal recessive	[3]
Hereditary spastic paraplegia 23	DISR7JN1	Supportive	Autosomal recessive	[4]
Renal agenesis, unilateral	DIS53ZJ8	Supportive	Autosomal dominant	[1]

4 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 Dual serine/threonine and tyrosine protein kinase (DSTYK).	[5]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Dual serine/threonine and tyrosine protein kinase (DSTYK).	[6]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Dual serine/threonine and tyrosine protein kinase (DSTYK).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Dual serine/threonine and tyrosine protein kinase (DSTYK).	[9]

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 decreases the methylation of Dual serine/threonine and tyrosine protein kinase (DSTYK).	[7]

References

• [1] Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med. 2013 Aug 15;369(7):621-9. doi: 10.1056/NEJMoa1214479. Epub 2013 Jul 17.
• [2] A locus for complicated hereditary spastic paraplegia maps to chromosome 1q24-q32.Ann Neurol. 2003 Dec;54(6):796-803. doi: 10.1002/ana.10768.
• [3] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [4] Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23. Am J Hum Genet. 2017 Feb 2;100(2):364-370. doi: 10.1016/j.ajhg.2017.01.014.
• [5] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [6] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [7] 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.
• [8] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [9] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.