Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZO6F1X)

DOT Name Pro-neuregulin-1, membrane-bound isoform (NRG1)
Synonyms Pro-NRG1
Gene Name NRG1
Related Disease
Schizophrenia 6 ( )
UniProt ID
NRG1_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1HAE; 1HAF; 1HRE; 1HRF; 3U7U; 7MN5; 7MN6; 7MN8; 7SJL
Pfam ID
PF00008 ; PF07679 ; PF02158
Sequence
MSERKEGRGKGKGKKKERGSGKKPESAAGSQSPALPPRLKEMKSQESAAGSKLVLRCETS
SEYSSLRFKWFKNGNELNRKNKPQNIKIQKKPGKSELRINKASLADSGEYMCKVISKLGN
DSASANITIVESNEIITGMPASTEGAYVSSESPIRISVSTEGANTSSSTSTSTTGTSHLV
KCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCQPGFTGARCTENVPMKVQNQEKAEELYQ
KRVLTITGICIALLVVGIMCVVAYCKTKKQRKKLHDRLRQSLRSERNNMMNIANGPHHPN
PPPENVQLVNQYVSKNVISSEHIVEREAETSFSTSHYTSTAHHSTTVTQTPSHSWSNGHT
ESILSESHSVIVMSSVENSRHSSPTGGPRGRLNGTGGPRECNSFLRHARETPDSYRDSPH
SERYVSAMTTPARMSPVDFHTPSSPKSPPSEMSPPVSSMTVSMPSMAVSPFMEEERPLLL
VTPPRLREKKFDHHPQQFSSFHHNPAHDSNSLPASPLRIVEDEEYETTQEYEPAQEPVKK
LANSRRAKRTKPNGHIANRLEVDSNTSSQSSNSESETEDERVGEDTPFLGIQNPLAASLE
ATPAFRLADSRTNPAGRFSTQEEIQARLSSVIANQDPIAV
Function
Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors. Concomitantly recruits ERBB1 and ERBB2 coreceptors, resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors. The multiple isoforms perform diverse functions such as inducing growth and differentiation of epithelial, glial, neuronal, and skeletal muscle cells; inducing expression of acetylcholine receptor in synaptic vesicles during the formation of the neuromuscular junction; stimulating lobuloalveolar budding and milk production in the mammary gland and inducing differentiation of mammary tumor cells; stimulating Schwann cell proliferation; implication in the development of the myocardium such as trabeculation of the developing heart. Isoform 10 may play a role in motor and sensory neuron development. Binds to ERBB4. Binds to ERBB3. Acts as a ligand for integrins and binds (via EGF domain) to integrins ITGAV:ITGB3 or ITGA6:ITGB4. Its binding to integrins and subsequent ternary complex formation with integrins and ERRB3 are essential for NRG1-ERBB signaling. Induces the phosphorylation and activation of MAPK3/ERK1, MAPK1/ERK2 and AKT1. Ligand-dependent ERBB4 endocytosis is essential for the NRG1-mediated activation of these kinases in neurons.
Tissue Specificity
Type I isoforms are the predominant forms expressed in the endocardium. Isoform alpha is expressed in breast, ovary, testis, prostate, heart, skeletal muscle, lung, placenta liver, kidney, salivary gland, small intestine and brain, but not in uterus, stomach, pancreas, and spleen. Isoform 3 is the predominant form in mesenchymal cells and in non-neuronal organs, whereas isoform 6 is the major neuronal form. Isoform 8 is expressed in spinal cord and brain. Isoform 9 is the major form in skeletal muscle cells; in the nervous system it is expressed in spinal cord and brain. Also detected in adult heart, placenta, lung, liver, kidney, and pancreas. Isoform 10 is expressed in nervous system: spinal cord motor neurons, dorsal root ganglion neurons, and brain. Predominant isoform expressed in sensory and motor neurons. Not detected in adult heart, placenta, lung, liver, skeletal muscle, kidney, and pancreas. Not expressed in fetal lung, liver and kidney. Type IV isoforms are brain-specific.
KEGG Pathway
EGFR tyrosine ki.se inhibitor resistance (hsa01521 )
ErbB sig.ling pathway (hsa04012 )
Amyotrophic lateral sclerosis (hsa05014 )
Reactome Pathway
(Name not found )
SHC1 events in ERBB4 signaling (R-HSA-1250347 )
Nuclear signaling by ERBB4 (R-HSA-1251985 )
GRB2 events in ERBB2 signaling (R-HSA-1963640 )
Long-term potentiation (R-HSA-9620244 )
PI3K events in ERBB4 signaling (R-HSA-1250342 )

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Schizophrenia 6 DISD0QQ4 Limited Autosomal recessive [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 4 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Marinol DM70IK5 Approved Pro-neuregulin-1, membrane-bound isoform (NRG1) affects the response to substance of Marinol. [37]
Fluorouracil DMUM7HZ Approved Pro-neuregulin-1, membrane-bound isoform (NRG1) affects the response to substance of Fluorouracil. [38]
Methamphetamine DMPM4SK Approved Pro-neuregulin-1, membrane-bound isoform (NRG1) affects the response to substance of Methamphetamine. [39]
GDC0941 DM1YAK6 Phase 2 Pro-neuregulin-1, membrane-bound isoform (NRG1) decreases the response to substance of GDC0941. [40]
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5 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 Pro-neuregulin-1, membrane-bound isoform (NRG1). [2]
Fulvestrant DM0YZC6 Approved Fulvestrant increases the methylation of Pro-neuregulin-1, membrane-bound isoform (NRG1). [14]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the methylation of Pro-neuregulin-1, membrane-bound isoform (NRG1). [25]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the methylation of Pro-neuregulin-1, membrane-bound isoform (NRG1). [29]
Coumarin DM0N8ZM Investigative Coumarin decreases the phosphorylation of Pro-neuregulin-1, membrane-bound isoform (NRG1). [31]
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32 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [3]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [4]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [5]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [6]
Arsenic DMTL2Y1 Approved Arsenic increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [7]
Temozolomide DMKECZD Approved Temozolomide increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [8]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [9]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [10]
Methotrexate DM2TEOL Approved Methotrexate increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [11]
Zoledronate DMIXC7G Approved Zoledronate decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [12]
Phenobarbital DMXZOCG Approved Phenobarbital affects the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [13]
Panobinostat DM58WKG Approved Panobinostat decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [10]
Cannabidiol DM0659E Approved Cannabidiol increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [15]
Troglitazone DM3VFPD Approved Troglitazone increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [16]
Etoposide DMNH3PG Approved Etoposide increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [17]
Clozapine DMFC71L Approved Clozapine increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [18]
Gemcitabine DMSE3I7 Approved Gemcitabine increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [19]
Cyclophosphamide DM4O2Z7 Approved Cyclophosphamide increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [20]
Dinoprostone DMTYOPD Approved Dinoprostone increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [21]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [10]
Resveratrol DM3RWXL Phase 3 Resveratrol decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [22]
Epigallocatechin gallate DMCGWBJ Phase 3 Epigallocatechin gallate decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [23]
Amiodarone DMUTEX3 Phase 2/3 Trial Amiodarone increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [24]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [26]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [27]
Scriptaid DM9JZ21 Preclinical Scriptaid affects the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [28]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [30]
Sulforaphane DMQY3L0 Investigative Sulforaphane increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [32]
3R14S-OCHRATOXIN A DM2KEW6 Investigative 3R14S-OCHRATOXIN A decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [33]
Nickel chloride DMI12Y8 Investigative Nickel chloride increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [34]
Hydroxydimethylarsine Oxide DMPS2B1 Investigative Hydroxydimethylarsine Oxide increases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [35]
SC-560 DMT1GJL Investigative SC-560 decreases the expression of Pro-neuregulin-1, membrane-bound isoform (NRG1). [36]
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⏷ Show the Full List of 32 Drug(s)

References

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