Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9L6C41)

• DOT Name: Receptor tyrosine-protein kinase erbB-4 (ERBB4)
• Synonyms: EC 2.7.10.1; Proto-oncogene-like protein c-ErbB-4; Tyrosine kinase-type cell surface receptor HER4; p180erbB4
• Gene Name: ERBB4
• Related Disease:
  Amyotrophic lateral sclerosis type 19
  Amyotrophic lateral sclerosis
• UniProt ID: ERBB4_HUMAN
• PDB ID: 2AHX; 2L2T; 2LCX; 2R4B; 3BBT; 3BBW; 3BCE; 3U2P; 3U7U; 3U9U
• EC Number: 2.7.10.1
• Pfam ID: PF00757 ; PF14843 ; PF07714 ; PF01030 ; PF21314
• Sequence:
  MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVM
  GNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIF
  LNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST
  NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSG
  PKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVD
  SSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT
  KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNL
  VTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFST
  INQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD
  GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGA
  NSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGG
  LFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR
  VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHL
  VRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLV
  HRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ
  SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMID
  ADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAE
  EYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP
  YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERS
  PRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAED
  EYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ
  EYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV
• Function: Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.
• Tissue Specificity: Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  ErbB sig.ling pathway (hsa04012)
  Calcium sig.ling pathway (hsa04020)
  PI3K-Akt sig.ling pathway (hsa04151)
  Amyotrophic lateral sclerosis (hsa05014)
  Proteoglycans in cancer (hsa05205)
• Reactome Pathway:
  Signaling by ERBB4 (R-HSA-1236394)
  SHC1 events in ERBB2 signaling (R-HSA-1250196)
  PI3K events in ERBB4 signaling (R-HSA-1250342)
  SHC1 events in ERBB4 signaling (R-HSA-1250347)
  Nuclear signaling by ERBB4 (R-HSA-1251985)
  Downregulation of ERBB4 signaling (R-HSA-1253288)
  PIP3 activates AKT signaling (R-HSA-1257604)
  GRB2 events in ERBB2 signaling (R-HSA-1963640)
  PI3K events in ERBB2 signaling (R-HSA-1963642)
  Constitutive Signaling by Aberrant PI3K in Cancer (R-HSA-2219530)
  RAF/MAP kinase cascade (R-HSA-5673001)
  ERBB2 Regulates Cell Motility (R-HSA-6785631)
  PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling (R-HSA-6811558)
  ERBB2 Activates PTK6 Signaling (R-HSA-8847993)
  Downregulation of ERBB2 signaling (R-HSA-8863795)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Long-term potentiation (R-HSA-9620244)
  Signaling by ERBB2 KD Mutants (R-HSA-9664565)
  Signaling by ERBB2 TMD/JMD mutants (R-HSA-9665686)
  Signaling by ERBB2 (R-HSA-1227986)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amyotrophic lateral sclerosis type 19	DISK9OIQ	Strong	Autosomal dominant	[1]
Amyotrophic lateral sclerosis	DISF7HVM	Supportive	Autosomal dominant	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[5]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[8]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[10]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[11]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[12]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[13]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[14]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[18]
PMID25656651-Compound-5	DMAI95U	Patented	PMID25656651-Compound-5 decreases the activity of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[19]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[21]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[22]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[23]
27-hydroxycholesterol	DM2L6OZ	Investigative	27-hydroxycholesterol decreases the expression of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[6]
PD-158780	DMQXYE9	Investigative	PD-158780 decreases the activity of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[17]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[20]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ibuprofen	DM8VCBE	Approved	Ibuprofen affects the cleavage of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[15]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the cleavage of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[16]
Pervanadate	DM873BS	Investigative	Pervanadate increases the cleavage of Receptor tyrosine-protein kinase erbB-4 (ERBB4).	[16]

References

• [1] ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. Am J Hum Genet. 2013 Nov 7;93(5):900-5. doi: 10.1016/j.ajhg.2013.09.008. Epub 2013 Oct 10.
• [2] 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.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol. 2008 Jan;22(1):65-77. doi: 10.1210/me.2007-0383. Epub 2007 Sep 13.
• [7] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [8] Arsenic trioxide and cisplatin synergism increase cytotoxicity in human ovarian cancer cells: therapeutic potential for ovarian cancer. Cancer Sci. 2009 Dec;100(12):2459-64.
• [9] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [10] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [11] Glucocorticoids inhibit cell death in ovarian cancer and up-regulate caspase inhibitor cIAP2. Clin Cancer Res. 2005 Sep 1;11(17):6325-32. doi: 10.1158/1078-0432.CCR-05-0182.
• [12] The DNA damaging agent VP16 induces the expression of a subset of ligands from the EGF system in bladder cancer cells, whereas none of the four EGF receptors are induced. Mol Cell Biochem. 2004 May;260(1-2):129-35. doi: 10.1023/b:mcbi.0000026063.96267.98.
• [13] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [14] 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.
• [15] Abeta42-lowering nonsteroidal anti-inflammatory drugs preserve intramembrane cleavage of the amyloid precursor protein (APP) and ErbB-4 receptor and signaling through the APP intracellular domain. J Biol Chem. 2003 Aug 15;278(33):30748-54. doi: 10.1074/jbc.M304824200. Epub 2003 May 31.
• [16] Tyrosine phosphorylation and proteolysis. Pervanadate-induced, metalloprotease-dependent cleavage of the ErbB-4 receptor and amphiregulin. J Biol Chem. 1998 Aug 7;273(32):20589-95. doi: 10.1074/jbc.273.32.20589.
• [17] 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.
• [18] 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.
• [19] AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009 Nov 6;16(5):401-12. doi: 10.1016/j.ccr.2009.09.028.
• [20] 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.
• [21] 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.
• [22] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.
• [23] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [24] G1 cell cycle arrest due to the inhibition of erbB family receptor tyrosine kinases does not require the retinoblastoma protein. Exp Cell Res. 2005 Feb 1;303(1):56-67. doi: 10.1016/j.yexcr.2004.08.040.