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

DOT Name Delta-like protein 1 (DLL1)
Synonyms Drosophila Delta homolog 1; Delta1; H-Delta-1
Gene Name DLL1
Related Disease
Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures ( )
Autosomal dominant non-syndromic intellectual disability ( )
Intellectual disability, autosomal dominant 40 ( )
UniProt ID
DLL1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
4XBM
Pfam ID
PF21700 ; PF01414 ; PF00008 ; PF07657
Sequence
MGSRCALALAVLSALLCQVWSSGVFELKLQEFVNKKGLLGNRNCCRGGAGPPPCACRTFF
RVCLKHYQASVSPEPPCTYGSAVTPVLGVDSFSLPDGGGADSAFSNPIRFPFGFTWPGTF
SLIIEALHTDSPDDLATENPERLISRLATQRHLTVGEEWSQDLHSSGRTDLKYSYRFVCD
EHYYGEGCSVFCRPRDDAFGHFTCGERGEKVCNPGWKGPYCTEPICLPGCDEQHGFCDKP
GECKCRVGWQGRYCDECIRYPGCLHGTCQQPWQCNCQEGWGGLFCNQDLNYCTHHKPCKN
GATCTNTGQGSYTCSCRPGYTGATCELGIDECDPSPCKNGGSCTDLENSYSCTCPPGFYG
KICELSAMTCADGPCFNGGRCSDSPDGGYSCRCPVGYSGFNCEKKIDYCSSSPCSNGAKC
VDLGDAYLCRCQAGFSGRHCDDNVDDCASSPCANGGTCRDGVNDFSCTCPPGYTGRNCSA
PVSRCEHAPCHNGATCHERGHRYVCECARGYGGPNCQFLLPELPPGPAVVDLTEKLEGQG
GPFPWVAVCAGVILVLMLLLGCAAVVVCVRLRLQKHRPPADPCRGETETMNNLANCQREK
DISVSIIGATQIKNTNKKADFHGDHSADKNGFKARYPAVDYNLVQDLKGDDTAVRDAHSK
RDTKCQPQGSSGEEKGTPTTLRGGEASERKRPDSGCSTSKDTKYQSVYVISEEKDECVIA
TEV
Function
Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner. Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation. Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells. Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor. Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation through regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis.
Tissue Specificity Expressed in heart and pancreas, with lower expression in brain and muscle and almost no expression in placenta, lung, liver and kidney.
KEGG Pathway
Endocrine resistance (hsa01522 )
Notch sig.ling pathway (hsa04330 )
Th1 and Th2 cell differentiation (hsa04658 )
Pathways in cancer (hsa05200 )
Chemical carcinogenesis - receptor activation (hsa05207 )
Breast cancer (hsa05224 )
Reactome Pathway
Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606 )
Constitutive Signaling by NOTCH1 t(7 (R-HSA-2660826 )
Constitutive Signaling by NOTCH1 HD Domain Mutants (R-HSA-2691232 )
Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862 )
NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096 )
NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507 )
MECP2 regulates transcription of neuronal ligands (R-HSA-9022702 )
Formation of paraxial mesoderm (R-HSA-9793380 )
Somitogenesis (R-HSA-9824272 )
M1580_K2555) Translocation Mutant (9)(NOTCH1 )
Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948 )

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Neurodevelopmental disorder with nonspecific brain abnormalities and with or without seizures DISOQBIL Strong Autosomal dominant [1]
Autosomal dominant non-syndromic intellectual disability DISD6L06 Supportive Autosomal dominant [2]
Intellectual disability, autosomal dominant 40 DISAI0IH Limited Autosomal dominant [2]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
2 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 Delta-like protein 1 (DLL1). [3]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Delta-like protein 1 (DLL1). [11]
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12 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 Delta-like protein 1 (DLL1). [4]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate affects the expression of Delta-like protein 1 (DLL1). [5]
Cisplatin DMRHGI9 Approved Cisplatin affects the expression of Delta-like protein 1 (DLL1). [6]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Delta-like protein 1 (DLL1). [7]
Temozolomide DMKECZD Approved Temozolomide increases the expression of Delta-like protein 1 (DLL1). [8]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of Delta-like protein 1 (DLL1). [9]
Decitabine DMQL8XJ Approved Decitabine affects the expression of Delta-like protein 1 (DLL1). [6]
Urethane DM7NSI0 Phase 4 Urethane decreases the expression of Delta-like protein 1 (DLL1). [10]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of Delta-like protein 1 (DLL1). [9]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Delta-like protein 1 (DLL1). [12]
Acetaldehyde DMJFKG4 Investigative Acetaldehyde increases the expression of Delta-like protein 1 (DLL1). [13]
Glyphosate DM0AFY7 Investigative Glyphosate increases the expression of Delta-like protein 1 (DLL1). [14]
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⏷ Show the Full List of 12 Drug(s)

References

1 De novo gene disruptions in children on the autistic spectrum. Neuron. 2012 Apr 26;74(2):285-99. doi: 10.1016/j.neuron.2012.04.009.
2 Haploinsufficiency of the Notch Ligand DLL1 Causes Variable Neurodevelopmental Disorders. Am J Hum Genet. 2019 Sep 5;105(3):631-639. doi: 10.1016/j.ajhg.2019.07.002. Epub 2019 Jul 25.
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 Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
5 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
6 Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
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 Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
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 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
11 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.
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.
13 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.
14 Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.