Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ3WWZH)

• DOT Name: Tyrosine-protein kinase RYK (RYK)
• Synonyms: EC 2.7.10.1
• Gene Name: RYK
• Related Disease:
  Acute leukaemia
  Advanced cancer
  Cleft lip
  Cleft lip/palate
  Cleft palate
  Epithelial ovarian cancer
  Glioma
  Isolated cleft lip
  Isolated cleft palate
  Neuralgia
  Ovarian cancer
  Ovarian neoplasm
  Refractory chronic myeloid leukaemia
  Pulmonary disease
  Familial medullary thyroid carcinoma
  Multiple endocrine neoplasia
  Multiple endocrine neoplasia type 2A
• UniProt ID: RYK_HUMAN
• PDB ID: 6TUA
• EC Number: 2.7.10.1
• Pfam ID: PF07714 ; PF02019
• Sequence:
  MRGAARLGRPGRSCLPGARGLRAPPPPPLLLLLALLPLLPAPGAAAAPAPRPPELQSASA
  GPSVSLYLSEDEVRRLIGLDAELYYVRNDLISHYALSFSLLVPSETNFLHFTWHAKSKVE
  YKLGFQVDNVLAMDMPQVNISVQGEVPRTLSVFRVELSCTGKVDSEVMILMQLNLTVNSS
  KNFTVLNFKRRKMCYKKLEEVKTSALDKNTSRTIYDPVHAAPTTSTRVFYISVGVCCAVI
  FLVAIILAVLHLHSMKRIELDDSISASSSSQGLSQPSTQTTQYLRADTPNNATPITSYPT
  LRIEKNDLRSVTLLEAKGKVKDIAISRERITLKDVLQEGTFGRIFHGILIDEKDPNKEKQ
  AFVKTVKDQASEIQVTMMLTESCKLRGLHHRNLLPITHVCIEEGEKPMVILPYMNWGNLK
  LFLRQCKLVEANNPQAISQQDLVHMAIQIACGMSYLARREVIHKDLAARNCVIDDTLQVK
  ITDNALSRDLFPMDYHCLGDNENRPVRWMALESLVNNEFSSASDVWAFGVTLWELMTLGQ
  TPYVDIDPFEMAAYLKDGYRIAQPINCPDELFAVMACCWALDPEERPKFQQLVQCLTEFH
  AALGAYV
• Function: May be a coreceptor along with FZD8 of Wnt proteins, such as WNT1, WNT3, WNT3A and WNT5A. Involved in neuron differentiation, axon guidance, corpus callosum establishment and neurite outgrowth. In response to WNT3 stimulation, receptor C-terminal cleavage occurs in its transmembrane region and allows the C-terminal intracellular product to translocate from the cytoplasm to the nucleus where it plays a crucial role in neuronal development.
• Tissue Specificity: Observed in all the tissues examined.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Axon guidance (hsa04360)
• Reactome Pathway:
  PCP/CE pathway (R-HSA-4086400)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Cleft lip	DISV3XW6	Strong	Genetic Variation	[3]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[3]
Cleft palate	DIS6G5TF	Strong	Genetic Variation	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[3]
Isolated cleft palate	DISV80CD	Strong	Genetic Variation	[3]
Neuralgia	DISWO58J	Strong	Biomarker	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[4]
Refractory chronic myeloid leukaemia	DIS40YPP	Strong	Genetic Variation	[7]
Pulmonary disease	DIS6060I	moderate	Biomarker	[8]
Familial medullary thyroid carcinoma	DIS01PWX	Limited	Genetic Variation	[9]
Multiple endocrine neoplasia	DISZGBKW	Limited	Genetic Variation	[9]
Multiple endocrine neoplasia type 2A	DIS7D3W2	Limited	Genetic Variation	[9]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Tyrosine-protein kinase RYK (RYK) affects the response to substance of Temozolomide.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Tyrosine-protein kinase RYK (RYK).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Tyrosine-protein kinase RYK (RYK).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Tyrosine-protein kinase RYK (RYK).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tyrosine-protein kinase RYK (RYK).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Tyrosine-protein kinase RYK (RYK).	[14]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Tyrosine-protein kinase RYK (RYK).	[15]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tyrosine-protein kinase RYK (RYK).	[18]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Tyrosine-protein kinase RYK (RYK).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Rigosertib	DMOSTXF	Phase 3	Rigosertib decreases the phosphorylation of Tyrosine-protein kinase RYK (RYK).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Tyrosine-protein kinase RYK (RYK).	[17]

References

• [1] WNT receptors profile expression in mature blood cells and immature leukemic cells: RYK emerges as a hallmark receptor of acute leukemia.Eur J Haematol. 2016 Aug;97(2):155-65. doi: 10.1111/ejh.12698. Epub 2015 Nov 30.
• [2] The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases.Growth Factors. 2018 Apr;36(1-2):15-40. doi: 10.1080/08977194.2018.1472089. Epub 2018 May 28.
• [3] A mutation in RYK is a genetic factor for nonsyndromic cleft lip and palate.Cleft Palate Craniofac J. 2006 May;43(3):310-6. doi: 10.1597/04-145.1.
• [4] H-RYK, an unusual receptor kinase: isolation and analysis of expression in ovarian cancer.Mol Med. 1996 Mar;2(2):189-203.
• [5] Ryk is essential for Wnt-5a-dependent invasiveness in human glioma.J Biochem. 2014 Jul;156(1):29-38. doi: 10.1093/jb/mvu015. Epub 2014 Mar 11.
• [6] Ryk receptors on unmyelinated nerve fibers mediate excitatory synaptic transmission and CCL2 release during neuropathic pain induced by peripheral nerve injury.Mol Pain. 2017 Jan-Dec;13:1744806917709372. doi: 10.1177/1744806917709372.
• [7] t(3;21)(q22;q22) leading to truncation of the RYK gene in atypical chronic myeloid leukemia.Cancer Lett. 2009 May 18;277(2):205-11. doi: 10.1016/j.canlet.2008.12.016. Epub 2009 Jan 24.
• [8] WNT/RYK signaling restricts goblet cell differentiation during lung development and repair.Proc Natl Acad Sci U S A. 2019 Dec 17;116(51):25697-25706. doi: 10.1073/pnas.1911071116. Epub 2019 Nov 27.
• [9] A potential pathogenetic mechanism for multiple endocrine neoplasia type 2 syndromes involves ret-induced impairment of terminal differentiation of neuroepithelial cells.Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7933-7. doi: 10.1073/pnas.93.15.7933.
• [10] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] 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.
• [14] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [15] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [16] Rigosertib as a selective anti-tumor agent can ameliorate multiple dysregulated signaling transduction pathways in high-grade myelodysplastic syndrome. Sci Rep. 2014 Dec 4;4:7310. doi: 10.1038/srep07310.
• [17] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [20] RYK Gene Expression Associated with Drug Response Variation of Temozolomide and Clinical Outcomes in Glioma Patients. Pharmaceuticals (Basel). 2023 May 10;16(5):726. doi: 10.3390/ph16050726.