Details of Drug Off-Target (DOT)

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

• DOT Name: Kremen protein 1 (KREMEN1)
• Synonyms: Dickkopf receptor; Kringle domain-containing transmembrane protein 1; Kringle-containing protein marking the eye and the nose
• Gene Name: KREMEN1
• Related Disease:
  Ankylosing spondylitis
  Spondyloarthropathy
  Ectodermal dysplasia
  Ectodermal dysplasia 13, hair/tooth type
  Neoplasm
  Plasma cell myeloma
  Schizophrenia
  Tooth agenesis
  Hyperostosis corticalis generalisata
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Enterovirus infection
  Parkinson disease
• UniProt ID: KREM1_HUMAN
• PDB ID: 5FWS; 5FWT; 5FWU; 5FWV; 5FWW; 7BZT; 7BZU
• Pfam ID: PF00431 ; PF00051 ; PF01822
• Sequence:
  MAPPAARLALLSAAALTLAARPAPSPGLGPECFTANGADYRGTQNWTALQGGKPCLFWNE
  TFQHPYNTLKYPNGEGGLGEHNYCRNPDGDVSPWCYVAEHEDGVYWKYCEIPACQMPGNL
  GCYKDHGNPPPLTGTSKTSNKLTIQTCISFCRSQRFKFAGMESGYACFCGNNPDYWKYGE
  AASTECNSVCFGDHTQPCGGDGRIILFDTLVGACGGNYSAMSSVVYSPDFPDTYATGRVC
  YWTIRVPGASHIHFSFPLFDIRDSADMVELLDGYTHRVLARFHGRSRPPLSFNVSLDFVI
  LYFFSDRINQAQGFAVLYQAVKEELPQERPAVNQTVAEVITEQANLSVSAARSSKVLYVI
  TTSPSHPPQTVPGSNSWAPPMGAGSHRVEGWTVYGLATLLILTVTAIVAKILLHVTFKSH
  RVPASGDLRDCHQPGTSGEIWSIFYKPSTSISIFKKKLKGQSQQDDRNPLVSD
• 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. In the absence of DKK1, potentiates Wnt-beta-catenin signaling by maintaining LRP5 or LRP6 at the cell membrane. Can trigger apoptosis in a Wnt-independent manner and this apoptotic activity is inhibited upon binding of the ligand DKK1. 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. Modulates cell fate decisions in the developing cochlea with an inhibitory role in hair cell fate specification.
• 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

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ankylosing spondylitis	DISRC6IR	Definitive	Biomarker	[1]
Spondyloarthropathy	DISBPYCZ	Definitive	Biomarker	[1]
Ectodermal dysplasia	DISLRS4M	Strong	Genetic Variation	[2]
Ectodermal dysplasia 13, hair/tooth type	DISPY9IT	Strong	Autosomal recessive	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[5]
Schizophrenia	DISSRV2N	Strong	Biomarker	[6]
Tooth agenesis	DIS1PWC7	Strong	Genetic Variation	[2]
Hyperostosis corticalis generalisata	DISR4BHB	Disputed	Genetic Variation	[7]
Aplasia cutis congenita	DISMDAYM	Limited	Genetic Variation	[8]
Corpus callosum, agenesis of	DISO9P40	Limited	Genetic Variation	[8]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[9]
Parkinson disease	DISQVHKL	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cycloheximide	DMGDA3C	Investigative	Kremen protein 1 (KREMEN1) affects the response to substance of Cycloheximide.	[23]

3 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 1 (KREMEN1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Kremen protein 1 (KREMEN1).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Kremen protein 1 (KREMEN1).	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Kremen protein 1 (KREMEN1).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Kremen protein 1 (KREMEN1).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Kremen protein 1 (KREMEN1).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Kremen protein 1 (KREMEN1).	[15]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Kremen protein 1 (KREMEN1).	[15]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Kremen protein 1 (KREMEN1).	[16]
Ethanol	DMDRQZU	Approved	Ethanol decreases the expression of Kremen protein 1 (KREMEN1).	[17]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of Kremen protein 1 (KREMEN1).	[18]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Kremen protein 1 (KREMEN1).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Kremen protein 1 (KREMEN1).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Kremen protein 1 (KREMEN1).	[22]

References

• [1] Expression profiling in spondyloarthropathy synovial biopsies highlights changes in expression of inflammatory genes in conjunction with tissue remodelling genes.BMC Musculoskelet Disord. 2013 Dec 15;14:354. doi: 10.1186/1471-2474-14-354.
• [2] Mutation of KREMEN1, a modulator of Wnt signaling, is responsible for ectodermal dysplasia including oligodontia in Palestinian families.Eur J Hum Genet. 2016 Oct;24(10):1430-5. doi: 10.1038/ejhg.2016.29. Epub 2016 Apr 6.
• [3] The Wnt signaling antagonist Kremen1 is required for development of thymic architecture. Clin Dev Immunol. 2006 Jun-Dec;13(2-4):299-319. doi: 10.1080/17402520600935097.
• [4] Kremen1 and Dickkopf1 control cell survival in a Wnt-independent manner.Cell Death Differ. 2016 Feb;23(2):323-32. doi: 10.1038/cdd.2015.100. Epub 2015 Jul 24.
• [5] Differential expression of DKK-1 binding receptors on stromal cells and myeloma cells results in their distinct response to secreted DKK-1 in myeloma.Mol Cancer. 2010 Sep 16;9:247. doi: 10.1186/1476-4598-9-247.
• [6] Genetic association study of KREMEN1 and DKK1 and schizophrenia in a Japanese population.Schizophr Res. 2010 May;118(1-3):113-7. doi: 10.1016/j.schres.2010.01.014. Epub 2010 Feb 11.
• [7] Genetic analysis and effect of triiodothyronine and prednisone trial on bone turnover in a patient with craniotubular hyperostosis.Bone. 2008 Aug;43(2):405-409. doi: 10.1016/j.bone.2008.04.011. Epub 2008 Apr 29.
• [8] Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma.J Clin Endocrinol Metab. 2015 Mar;100(3):E493-502. doi: 10.1210/jc.2014-3282. Epub 2014 Dec 9.
• [9] Structures of Coxsackievirus A10 unveil the molecular mechanisms of receptor binding and viral uncoating.Nat Commun. 2018 Nov 26;9(1):4985. doi: 10.1038/s41467-018-07531-0.
• [10] Identifying rare and common disease associated variants in genomic data using Parkinson's disease as a model.J Biomed Sci. 2014 Aug 30;21(1):88. doi: 10.1186/s12929-014-0088-9.
• [11] 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.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [14] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] 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.
• [17] Effects of acute ethanol treatment on NCCIT cells and NCCIT cell-derived embryoid bodies (EBs). Toxicol In Vitro. 2010 Sep;24(6):1696-704. doi: 10.1016/j.tiv.2010.05.017. Epub 2010 May 26.
• [18] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Population-based in vitro hazard and concentration-response assessment of chemicals: the 1000 genomes high-throughput screening study. Environ Health Perspect. 2015 May;123(5):458-66. doi: 10.1289/ehp.1408775. Epub 2015 Jan 13.