Details of Drug Off-Target (DOT)

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

• DOT Name: Dickkopf-related protein 2 (DKK2)
• Synonyms: Dickkopf-2; Dkk-2; hDkk-2
• Gene Name: DKK2
• UniProt ID: DKK2_HUMAN
• Pfam ID: PF04706 ; PF21481 ; PF21479
• Sequence:
  MAALMRSKDSSCCLLLLAAVLMVESSQIGSSRAKLNSIKSSLGGETPGQAANRSAGMYQG
  LAFGGSKKGKNLGQAYPCSSDKECEVGRYCHSPHQGSSACMVCRRKKKRCHRDGMCCPST
  RCNNGICIPVTESILTPHIPALDGTRHRDRNHGHYSNHDLGWQNLGRPHTKMSHIKGHEG
  DPCLRSSDCIEGFCCARHFWTKICKPVLHQGEVCTKQRKKGSHGLEIFQRCDCAKGLSCK
  VWKDATYSSKARLHVCQKI
• Function: Antagonizes canonical Wnt signaling by inhibiting LRP5/6 interaction with Wnt and by forming a ternary complex with the transmembrane protein KREMEN that promotes internalization of LRP5/6. DKKs play an important role in vertebrate development, where they locally inhibit Wnt regulated processes such as antero-posterior axial patterning, limb development, somitogenesis and eye formation. In the adult, Dkks are implicated in bone formation and bone disease, cancer and Alzheimer disease.
• Tissue Specificity: Expressed in heart, brain, skeletal muscle and lung.
• KEGG Pathway:
  Wnt sig.ling pathway (hsa04310)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  Negative regulation of TCF-dependent signaling by WNT ligand antagonists (R-HSA-3772470)
  Signaling by LRP5 mutants (R-HSA-5339717)
  TCF dependent signaling in response to WNT (R-HSA-201681)

Molecular Interaction Atlas (MIA) of This DOT

11 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 Dickkopf-related protein 2 (DKK2).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dickkopf-related protein 2 (DKK2).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Dickkopf-related protein 2 (DKK2).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Dickkopf-related protein 2 (DKK2).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Dickkopf-related protein 2 (DKK2).	[5]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Dickkopf-related protein 2 (DKK2).	[6]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Dickkopf-related protein 2 (DKK2).	[7]
Indomethacin	DMSC4A7	Approved	Indomethacin increases the expression of Dickkopf-related protein 2 (DKK2).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Dickkopf-related protein 2 (DKK2).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Dickkopf-related protein 2 (DKK2).	[1]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Dickkopf-related protein 2 (DKK2).	[11]

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 Dickkopf-related protein 2 (DKK2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Dickkopf-related protein 2 (DKK2).	[10]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [4] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [5] 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.
• [6] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [7] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [8] Evaluation of developmental toxicity using undifferentiated human embryonic stem cells. J Appl Toxicol. 2015 Feb;35(2):205-18.
• [9] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [10] 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.
• [11] Deguelin inhibits growth of breast cancer cells by modulating the expression of key members of the Wnt signaling pathway. Cancer Prev Res (Phila). 2009 Nov;2(11):942-50. doi: 10.1158/1940-6207.CAPR-08-0232. Epub 2009 Oct 27.