Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS0BTXC)

• DOT Name: Kremen protein 2 (KREMEN2)
• Synonyms: Dickkopf receptor 2; Kringle domain-containing transmembrane protein 2; Kringle-containing protein marking the eye and the nose
• Gene Name: KREMEN2
• Related Disease:
  Depression
  Osteoporosis
• UniProt ID: KREM2_HUMAN
• Pfam ID: PF00431 ; PF00051 ; PF01822
• Sequence:
  MGTQALQGFLFLLFLPLLQPRGASAGSLHSPGLSECFQVNGADYRGHQNRTGPRGAGRPC
  LFWDQTQQHSYSSASDPHGRWGLGAHNFCRNPDGDVQPWCYVAETEEGIYWRYCDIPSCH
  MPGYLGCFVDSGAPPALSGPSGTSTKLTVQVCLRFCRMKGYQLAGVEAGYACFCGSESDL
  ARGRLAPATDCDQICFGHPGQLCGGDGRLGVYEVSVGSCQGNWTAPQGVIYSPDFPDEYG
  PDRNCSWALGPPGAALELTFRLFELADPRDRLELRDAASGSLLRAFDGARPPPSGPLRLG
  TAALLLTFRSDARGHAQGFALTYRGLQDAAEDPEAPEGSAQTPAAPLDGANVSCSPRPGA
  PPAAIGARVFSTVTAVSVLLLLLLGLLRPLRRRSCLLAPGKGPPALGASRGPRRSWAVWY
  QQPRGVALPCSPGDPQAEGSAAGYRPLSASSQSSLRSLISAL
• Function: Receptor for Dickkopf proteins. Cooperates with DKK1/2 to inhibit Wnt/beta-catenin signaling by promoting the endocytosis of Wnt receptors LRP5 and LRP6. Plays a role in limb development; attenuates Wnt signaling in the developing limb to allow normal limb patterning and can also negatively regulate bone formation.
• 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

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Depression	DIS3XJ69	Strong	Biomarker	[1]
Osteoporosis	DISF2JE0	Strong	Biomarker	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Kremen protein 2 (KREMEN2).	[3]

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 Kremen protein 2 (KREMEN2).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Kremen protein 2 (KREMEN2).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Kremen protein 2 (KREMEN2).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Kremen protein 2 (KREMEN2).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Kremen protein 2 (KREMEN2).	[8]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Kremen protein 2 (KREMEN2).	[9]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Kremen protein 2 (KREMEN2).	[10]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kremen protein 2 (KREMEN2).	[11]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Kremen protein 2 (KREMEN2).	[12]

References

• [1] Effects of the 2/3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam.Behav Pharmacol. 2019 Aug;30(5):452-461. doi: 10.1097/FBP.0000000000000464.
• [2] Identification of novel genes associated with fracture healing in osteoporosis induced by Krm2 overexpression or Lrp5 deficiency.Mol Med Rep. 2017 Jun;15(6):3969-3976. doi: 10.3892/mmr.2017.6544. Epub 2017 May 3.
• [3] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [9] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [10] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [11] 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.
• [12] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.