Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH0Z1XV)

• DOT Name: Protein Wnt-10b
• Synonyms: Protein Wnt-12
• Gene Name: WNT10B
• Related Disease:
  Split hand-foot malformation 6
  Tooth agenesis, selective, 8
  Split hand-foot malformation
  Tooth agenesis
• UniProt ID: WN10B_HUMAN
• Pfam ID: PF00110
• Sequence:
  MLEEPRPRPPPSGLAGLLFLALCSRALSNEILGLKLPGEPPLTANTVCLTLSGLSKRQLG
  LCLRNPDVTASALQGLHIAVHECQHQLRDQRWNCSALEGGGRLPHHSAILKRGFRESAFS
  FSMLAAGVMHAVATACSLGKLVSCGCGWKGSGEQDRLRAKLLQLQALSRGKSFPHSLPSP
  GPGSSPSPGPQDTWEWGGCNHDMDFGEKFSRDFLDSREAPRDIQARMRIHNNRVGRQVVT
  ENLKRKCKCHGTSGSCQFKTCWRAAPEFRAVGAALRERLGRAIFIDTHNRNSGAFQPRLR
  PRRLSGELVYFEKSPDFCERDPTMGSPGTRGRACNKTSRLLDGCGSLCCGRGHNVLRQTR
  VERCHCRFHWCCYVLCDECKVTEWVNVCK
• Function: Member of the Wnt ligand gene family that encodes for secreted proteins, which activate the Wnt signaling cascade. Specifically activates canonical Wnt/beta-catenin signaling and thus triggers beta-catenin/LEF/TCF-mediated transcriptional programs. Involved in signaling networks controlling stemness, pluripotency and cell fate decisions. Acts in the immune system, mammary gland, adipose tissue, bone and skin.
• Tissue Specificity: Detected in most adult tissues. Highest levels were found in heart and skeletal muscle. Low levels are found in brain.
• KEGG Pathway:
  mTOR sig.ling pathway (hsa04150)
  Wnt sig.ling pathway (hsa04310)
  Hippo sig.ling pathway (hsa04390)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Melanogenesis (hsa04916)
  Cushing syndrome (hsa04934)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Basal cell carcinoma (hsa05217)
  Breast cancer (hsa05224)
  Hepatocellular carcinoma (hsa05225)
  Gastric cancer (hsa05226)
• Reactome Pathway:
  Class B/2 (Secretin family receptors) (R-HSA-373080)
  Transcriptional regulation of white adipocyte differentiation (R-HSA-381340)
  WNT ligand biogenesis and trafficking (R-HSA-3238698)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Split hand-foot malformation 6	DISOLIHQ	Definitive	Autosomal recessive	[1]
Tooth agenesis, selective, 8	DISAN669	Moderate	Autosomal dominant	[2]
Split hand-foot malformation	DIS8PKGD	Supportive	Autosomal dominant	[3]
Tooth agenesis	DIS1PWC7	Supportive	Autosomal dominant	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Wnt-10b.	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein Wnt-10b.	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein Wnt-10b.	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein Wnt-10b.	[8]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein Wnt-10b.	[9]
Permethrin	DMZ0Q1G	Approved	Permethrin increases the expression of Protein Wnt-10b.	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein Wnt-10b.	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein Wnt-10b.	[11]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein Wnt-10b.	[12]

References

• [1] Evidence for autosomal recessive inheritance of split hand/split foot malformation: a report of nine cases. Clin Dysmorphol. 2002 Jul;11(3):183-6. doi: 10.1097/00019605-200207000-00006.
• [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] Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation. Hum Mol Genet. 2008 Sep 1;17(17):2644-53. doi: 10.1093/hmg/ddn164. Epub 2008 May 30.
• [4] Mutations in WNT10B Are Identified in Individuals with Oligodontia. Am J Hum Genet. 2016 Jul 7;99(1):195-201. doi: 10.1016/j.ajhg.2016.05.012. Epub 2016 Jun 16.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Effects of pyrethroid insecticides and estrogen on WNT10B proto-oncogene expression. Environ Int. 2002 Nov;28(5):429-32. doi: 10.1016/s0160-4120(02)00072-7.
• [8] 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.
• [9] 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.
• [10] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [11] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [12] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.