General Information of Target

Target ID LDTP06353
Target Name Receptor tyrosine-protein kinase erbB-4 (ERBB4)
Gene Name ERBB4
Gene ID 2066
Synonyms
HER4; Receptor tyrosine-protein kinase erbB-4; EC 2.7.10.1; Proto-oncogene-like protein c-ErbB-4; Tyrosine kinase-type cell surface receptor HER4; p180erbB4) [Cleaved into: ERBB4 intracellular domain; 4ICD; E4ICD; s80HER4)]
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MKPATGLWVWVSLLVAAGTVQPSDSQSVCAGTENKLSSLSDLEQQYRALRKYYENCEVVM
GNLEITSIEHNRDLSFLRSVREVTGYVLVALNQFRYLPLENLRIIRGTKLYEDRYALAIF
LNYRKDGNFGLQELGLKNLTEILNGGVYVDQNKFLCYADTIHWQDIVRNPWPSNLTLVST
NGSSGCGRCHKSCTGRCWGPTENHCQTLTRTVCAEQCDGRCYGPYVSDCCHRECAGGCSG
PKDTDCFACMNFNDSGACVTQCPQTFVYNPTTFQLEHNFNAKYTYGAFCVKKCPHNFVVD
SSSCVRACPSSKMEVEENGIKMCKPCTDICPKACDGIGTGSLMSAQTVDSSNIDKFINCT
KINGNLIFLVTGIHGDPYNAIEAIDPEKLNVFRTVREITGFLNIQSWPPNMTDFSVFSNL
VTIGGRVLYSGLSLLILKQQGITSLQFQSLKEISAGNIYITDNSNLCYYHTINWTTLFST
INQRIVIRDNRKAENCTAEGMVCNHLCSSDGCWGPGPDQCLSCRRFSRGRICIESCNLYD
GEFREFENGSICVECDPQCEKMEDGLLTCHGPGPDNCTKCSHFKDGPNCVEKCPDGLQGA
NSFIFKYADPDRECHPCHPNCTQGCNGPTSHDCIYYPWTGHSTLPQHARTPLIAAGVIGG
LFILVIVGLTFAVYVRRKSIKKKRALRRFLETELVEPLTPSGTAPNQAQLRILKETELKR
VKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDHPHL
VRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEERRLV
HRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKFTHQ
SDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCWMID
ADSRPKFKELAAEFSRMARDPQRYLVIQGDDRMKLPSPNDSKFFQNLLDEEDLEDMMDAE
EYLVPQAFNIPPPIYTSRARIDSNRSEIGHSPPPAYTPMSGNQFVYRDGGFAAEQGVSVP
YRAPTSTIPEAPVAQGATAEIFDDSCCNGTLRKPVAPHVQEDSSTQRYSADPTVFAPERS
PRGELDEEGYMTPMRDKPKQEYLNPVEENPFVSRRKNGDLQALDNPEYHNASNGPPKAED
EYVNEPLYLNTFANTLGKAEYLKNNILSMPEKAKKAFDNPDYWNHSLPPRSTLQHPDYLQ
EYSTKYFYKQNGRIRPIVAENPEYLSEFSLKPGTVLPPPPYRHRNTVV
Target Type
Successful
Target Bioclass
Enzyme
Family
Protein kinase superfamily, Tyr protein kinase family, EGF receptor subfamily
Subcellular location
Nucleus; Cell membrane
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.
TTD ID
T92057
Uniprot ID
Q15303
DrugMap ID
TT0JESD
Ensemble ID
ENST00000260943.11
HGNC ID
HGNC:3432
ChEMBL ID
CHEMBL3009

Target Site Mutations in Different Cell Lines

Cell line Mutation details Probe for labeling this protein in this cell
CAL148 SNV: p.M250I DBIA    Probe Info 
CCK81 SNV: p.L780P .
CHL1 SNV: p.C945F; p.A1083V .
COLO679 SNV: p.G127E .
COLO792 SNV: p.M313I
Substitution: p.G730K
DBIA    Probe Info 
FTC133 SNV: p.V748L DBIA    Probe Info 
GB1 SNV: p.T394S DBIA    Probe Info 
HCC15 SNV: p.G816A DBIA    Probe Info 
HCT15 SNV: p.L369I .
HEC1 SNV: p.L770P DBIA    Probe Info 
HEC1B SNV: p.L770P .
HGC27 SNV: p.M775I DBIA    Probe Info 
HT SNV: p.T639A .
HT115 SNV: p.R1273Q .
IGR1 SNV: p.W171Ter .
J82 SNV: p.R1045G DBIA    Probe Info 
JURKAT SNV: p.N253K; p.M1154V .
KELLY SNV: p.P386S DBIA    Probe Info 
KMS27 SNV: p.P294Q .
KPL1 SNV: p.Y1242C DBIA    Probe Info 
MCC13 SNV: p.G127E; p.T1215I DBIA    Probe Info 
MCF7 SNV: p.Y1242C .
MEWO SNV: p.S449F; p.M766I DBIA    Probe Info 
MFE319 SNV: p.A978T DBIA    Probe Info 
MOLT4 SNV: p.A287T .
NCIH2172 SNV: p.G668V DBIA    Probe Info 
NCIH2291 SNV: p.G107V; p.P309S DBIA    Probe Info 
REH SNV: p.E1100V .
RL952 SNV: p.D960Y DBIA    Probe Info 
RPMI8226 SNV: p.F247C .
SHP77 SNV: p.G107V .
SNU1 SNV: p.G511C DBIA    Probe Info 
SUPT1 SNV: p.A4V .

Probe(s) Labeling This Target

ABPP Probe
Click To Hide/Show 2 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
OPA-S-S-alkyne
 Probe Info 
K109(1.90)  LDD3494  [1]
DBIA
 Probe Info 
C956(2.82)  LDD3310  [2]
PAL-AfBPP Probe
Click To Hide/Show 1 Probe Related to This Target
Probe name Structure Binding Site(Ratio) Interaction ID Ref
DFG-out-4
 Probe Info 
11.00  LDD0075  [3]

Competitor(s) Related to This Target

Competitor ID Name Cell line Binding Site(Ratio) Interaction ID Ref
 LDCM0017  DFG-out-2 A431 11.00  LDD0075  [3]
 LDCM0022  KB02 42-MG-BA C956(1.66)  LDD2244  [2]
 LDCM0023  KB03 42-MG-BA C956(3.55)  LDD2661  [2]
 LDCM0024  KB05 COLO792 C956(2.82)  LDD3310  [2]

The Interaction Atlas With This Target

The Protein(s) Related To This Target

Enzyme
Click To Hide/Show 4 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Tyrosine-protein kinase ABL2 (ABL2) Tyr protein kinase family P42684
Epidermal growth factor receptor (EGFR) Tyr protein kinase family P00533
Receptor tyrosine-protein kinase erbB-2 (ERBB2) Tyr protein kinase family P04626
Receptor tyrosine-protein kinase erbB-3 (ERBB3) Tyr protein kinase family P21860
Transporter and channel
Click To Hide/Show 2 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Heat shock protein HSP 90-beta (HSP90AB1) Heat shock protein 90 family P08238
Disks large homolog 4 (DLG4) MAGUK family P78352
Immunoglobulin
Click To Hide/Show 1 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) . Q96JA1
Other
Click To Hide/Show 6 Protein(s) Interacting with This Target
Protein name Family Uniprot ID
Bystin (BYSL) Bystin family Q13895
Protein S100-A4 (S100A4) S-100 family P26447
Transcriptional coactivator YAP1 (YAP1) YAP1 family P46937
Proheparin-binding EGF-like growth factor (HBEGF) . Q99075
SHC-transforming protein 1 (SHC1) . P29353
Tastin (TROAP) . Q12815

The Drug(s) Related To This Target

Approved
Click To Hide/Show 5 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Afatinib Small molecular drug DB08916
Brigatinib Small molecular drug DB12267
Dacomitinib Small molecular drug D06XXH
Fostamatinib Small molecular drug DB12010
Zanubrutinib . DB15035
Phase 3
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Rg7388 Small molecular drug D0OC4O
Phase 2
Click To Hide/Show 2 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Ci-1033 Small molecular drug D0YB3W
Ji-101 Small molecular drug D0Z7IW
Phase 1
Click To Hide/Show 1 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Jnj-26483327 . D0U3XL
Investigative
Click To Hide/Show 2 Drug(s) Interacting with This Target
Drug Name Drug Type External ID
Hds-029 Small molecular drug D05FFT
Pmid24915291c38 Small molecular drug D06BJG

References

1 A chemical proteomics approach for global mapping of functional lysines on cell surface of living cell. Nat Commun. 2024 Apr 8;15(1):2997. doi: 10.1038/s41467-024-47033-w.
Mass spectrometry data entry: PXD042888
2 DrugMap: A quantitative pan-cancer analysis of cysteine ligandability. Cell. 2024 May 9;187(10):2536-2556.e30. doi: 10.1016/j.cell.2024.03.027. Epub 2024 Apr 22.
Mass spectrometry data entry: PXD047840
3 Affinity-based probes based on type II kinase inhibitors. J Am Chem Soc. 2012 Nov 21;134(46):19017-25. doi: 10.1021/ja306035v. Epub 2012 Nov 6.