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Q15303

- ERBB4_HUMAN

UniProt

Q15303 - ERBB4_HUMAN

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Protein

Receptor tyrosine-protein kinase erbB-4

Gene

ERBB4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli

Functioni

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.22 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.4 PublicationsPROSITE-ProRule annotation

Enzyme regulationi

Binding of a cognate ligand leads to dimerization and activation by autophosphorylation on tyrosine residues. In vitro kinase activity is increased by Mg2+. Inhibited by PD153035, lapatinib, gefitinib (iressa, ZD1839), AG1478 and BIBX1382BS.5 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei751 – 7511ATPPROSITE-ProRule annotation
Active sitei843 – 8431Proton acceptorPROSITE-ProRule annotation

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi724 – 7329ATPPROSITE-ProRule annotation
Nucleotide bindingi797 – 7993ATPPROSITE-ProRule annotation
Nucleotide bindingi843 – 8486ATPPROSITE-ProRule annotation

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. epidermal growth factor receptor binding Source: UniProtKB
  3. protein homodimerization activity Source: UniProtKB
  4. protein tyrosine kinase activity Source: UniProtKB
  5. receptor signaling protein tyrosine kinase activity Source: InterPro
  6. transcription regulatory region DNA binding Source: UniProtKB
  7. transmembrane receptor protein tyrosine kinase activity Source: UniProtKB

GO - Biological processi

  1. cardiac muscle tissue regeneration Source: UniProtKB
  2. cell fate commitment Source: Ensembl
  3. cell migration Source: UniProtKB
  4. cell proliferation Source: ProtInc
  5. central nervous system morphogenesis Source: UniProtKB
  6. embryonic pattern specification Source: UniProtKB
  7. epidermal growth factor receptor signaling pathway Source: Reactome
  8. Fc-epsilon receptor signaling pathway Source: Reactome
  9. fibroblast growth factor receptor signaling pathway Source: Reactome
  10. heart development Source: UniProtKB
  11. innate immune response Source: Reactome
  12. lactation Source: UniProtKB
  13. mammary gland alveolus development Source: UniProtKB
  14. mammary gland epithelial cell differentiation Source: UniProtKB
  15. mitochondrial fragmentation involved in apoptotic process Source: UniProtKB
  16. negative regulation of apoptotic process Source: UniProtKB
  17. negative regulation of cell proliferation Source: UniProtKB
  18. nervous system development Source: UniProtKB
  19. neural crest cell migration Source: UniProtKB
  20. neurotrophin TRK receptor signaling pathway Source: Reactome
  21. olfactory bulb interneuron differentiation Source: UniProtKB
  22. peptidyl-tyrosine phosphorylation Source: UniProtKB
  23. phosphatidylinositol-mediated signaling Source: Reactome
  24. positive regulation of cardiac muscle cell proliferation Source: UniProtKB
  25. positive regulation of cell proliferation Source: UniProtKB
  26. positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  27. positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
  28. positive regulation of protein phosphorylation Source: UniProtKB
  29. positive regulation of STAT protein import into nucleus Source: UniProtKB
  30. positive regulation of transcription, DNA-templated Source: UniProtKB
  31. positive regulation of tyrosine phosphorylation of Stat5 protein Source: UniProtKB
  32. protein autophosphorylation Source: UniProtKB
  33. regulation of cell migration Source: UniProtKB
  34. signal transduction Source: UniProtKB
  35. transcription, DNA-templated Source: UniProtKB-KW
  36. transmembrane receptor protein tyrosine kinase signaling pathway Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Activator, Developmental protein, Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Apoptosis, Lactation, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 2681.
ReactomeiREACT_115596. Signaling by ERBB4.
REACT_115755. Signaling by ERBB2.
REACT_115828. Downregulation of ERBB4 signaling.
REACT_115854. GRB2 events in ERBB2 signaling.
REACT_115961. PI3K events in ERBB4 signaling.
REACT_115993. SHC1 events in ERBB2 signaling.
REACT_116005. SHC1 events in ERBB4 signaling.
REACT_116008. PI3K events in ERBB2 signaling.
REACT_116022. Nuclear signaling by ERBB4.
REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
REACT_75829. PIP3 activates AKT signaling.
SignaLinkiQ15303.

Names & Taxonomyi

Protein namesi
Recommended name:
Receptor tyrosine-protein kinase erbB-4 (EC:2.7.10.1)
Alternative name(s):
Proto-oncogene-like protein c-ErbB-4
Tyrosine kinase-type cell surface receptor HER4
p180erbB4
Cleaved into the following chain:
ERBB4 intracellular domain
Short name:
4ICD
Short name:
E4ICD
Alternative name(s):
s80HER4
Gene namesi
Name:ERBB4
Synonyms:HER4
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
ProteomesiUP000005640: Chromosome 2

Organism-specific databases

HGNCiHGNC:3432. ERBB4.

Subcellular locationi

Cell membrane 12 Publications; Single-pass type I membrane protein 12 Publications
Note: In response to NRG1 treatment, the activated receptor is internalized.
Chain ERBB4 intracellular domain : Nucleus 1 Publication. Mitochondrion 1 Publication
Note: Following proteolytical processing E4ICD (E4ICD1 or E4ICD2 generated from the respective isoforms) is translocated to the nucleus. Significantly more E4ICD2 than E4ICD1 is found in the nucleus. E4ICD2 colocalizes with YAP1 in the nucleus.

GO - Cellular componenti

  1. basolateral plasma membrane Source: BHF-UCL
  2. cytosol Source: Reactome
  3. extracellular region Source: Reactome
  4. integral component of membrane Source: UniProtKB-KW
  5. mitochondrial matrix Source: Reactome
  6. mitochondrion Source: UniProtKB
  7. nucleoplasm Source: Reactome
  8. nucleus Source: UniProtKB
  9. plasma membrane Source: Reactome
  10. receptor complex Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

Amyotrophic lateral sclerosis 19 (ALS19) [MIM:615515]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases.1 Publication
Note: The disease is caused by mutations affecting the gene represented in this entry.
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti927 – 9271R → Q in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
VAR_070810
Natural varianti1275 – 12751R → W in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
VAR_070811

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi646 – 6461Q → C: Constitutively activated kinase. 1 Publication
Mutagenesisi675 – 6751V → A: Abolishes proteolytic processing and nuclear localization. 2 Publications
Mutagenesisi681 – 6844KKKR → EIMG: Abolishes nuclear localization of the ERBB4 intracellular domain. 1 Publication
Mutagenesisi710 – 7101L → N: Strongly reduced autophosphorylation. 1 Publication
Mutagenesisi721 – 7211V → I: No effect on kinase activity. 1 Publication
Mutagenesisi751 – 7511K → R: Abolishes kinase activity. Abolishes phosphorylation, proteolytic processing and nuclear localization. 3 Publications
Mutagenesisi766 – 7661M → R: Strongly reduced autophosphorylation. 1 Publication
Mutagenesisi773 – 7731A → S: No effect on kinase activity. 1 Publication
Mutagenesisi782 – 7821R → Q: No effect on kinase activity. 1 Publication
Mutagenesisi810 – 8101E → K: No effect on kinase activity. 1 Publication
Mutagenesisi843 – 8431D → N: Loss of kinase activity. 1 Publication
Mutagenesisi854 – 8541P → Q: No effect on kinase activity. 1 Publication
Mutagenesisi861 – 8611D → Y: Loss of kinase activity. 1 Publication
Mutagenesisi864 – 8641L → R: Strongly reduced autophosphorylation. 1 Publication
Mutagenesisi872 – 8721E → K: No effect on kinase activity. 1 Publication
Mutagenesisi926 – 9261T → M: No effect on kinase activity. 1 Publication
Mutagenesisi947 – 9471I → R: Constitutively autophosphorylated. 1 Publication
Mutagenesisi992 – 9921R → A: Abolishes APC/C-mediated degradation; when associated with A-995 and A-1000. 1 Publication
Mutagenesisi995 – 9951L → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-1000. 1 Publication
Mutagenesisi1000 – 10001D → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-995. 1 Publication
Mutagenesisi1035 – 10351Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1301. 1 Publication
Mutagenesisi1056 – 10561Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. Promotes nuclear translocation of ERBB4 intracellular domain E4ICD1. 1 Publication
Mutagenesisi1056 – 10561Y → F: Abolishes interaction with WWP1; when associated with F-1301. 1 Publication
Mutagenesisi1301 – 13011Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. 3 Publications
Mutagenesisi1301 – 13011Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1035. Loss of interaction with YAP1 and stimulation of transcription. 3 Publications
Mutagenesisi1301 – 13011Y → F: Abolishes interaction with WWP1; when associated with F-1056. 3 Publications

Keywords - Diseasei

Amyotrophic lateral sclerosis, Disease mutation, Neurodegeneration

Organism-specific databases

MIMi615515. phenotype.
Orphaneti803. Amyotrophic lateral sclerosis.
PharmGKBiPA27847.

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2525Sequence AnalysisAdd
BLAST
Chaini26 – 13081283Receptor tyrosine-protein kinase erbB-4PRO_0000016674Add
BLAST
Chaini676 – 1308633ERBB4 intracellular domainBy similarityPRO_0000396797Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Disulfide bondi29 ↔ 561 Publication
Glycosylationi138 – 1381N-linked (GlcNAc...)1 Publication
Disulfide bondi156 ↔ 1861 Publication
Glycosylationi174 – 1741N-linked (GlcNAc...)1 Publication
Glycosylationi181 – 1811N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi189 ↔ 1971 Publication
Disulfide bondi193 ↔ 2051 Publication
Disulfide bondi213 ↔ 2211 Publication
Disulfide bondi217 ↔ 2291 Publication
Disulfide bondi230 ↔ 2381 Publication
Disulfide bondi234 ↔ 2461 Publication
Disulfide bondi249 ↔ 2581 Publication
Glycosylationi253 – 2531N-linked (GlcNAc...)1 Publication
Disulfide bondi262 ↔ 2891 Publication
Disulfide bondi293 ↔ 3041 Publication
Disulfide bondi308 ↔ 3231 Publication
Disulfide bondi326 ↔ 3301 Publication
Glycosylationi358 – 3581N-linked (GlcNAc...)1 Publication
Glycosylationi410 – 4101N-linked (GlcNAc...)1 Publication
Glycosylationi473 – 4731N-linked (GlcNAc...)1 Publication
Glycosylationi495 – 4951N-linked (GlcNAc...)1 Publication
Disulfide bondi503 ↔ 5121 Publication
Disulfide bondi507 ↔ 5201 Publication
Disulfide bondi523 ↔ 5321 Publication
Disulfide bondi536 ↔ 5521 Publication
Glycosylationi548 – 5481N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi555 ↔ 5691 Publication
Disulfide bondi559 ↔ 5771 Publication
Glycosylationi576 – 5761N-linked (GlcNAc...)1 Publication
Disulfide bondi580 ↔ 5891 Publication
Disulfide bondi593 ↔ 6141 Publication
Disulfide bondi617 ↔ 6251 Publication
Glycosylationi620 – 6201N-linked (GlcNAc...)Sequence Analysis
Disulfide bondi621 ↔ 6331 Publication
Modified residuei875 – 8751Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1035 – 10351Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1056 – 10561Phosphotyrosine; by autocatalysis3 Publications
Modified residuei1150 – 11501Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1162 – 11621Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1188 – 11881Phosphotyrosine; by autocatalysis2 Publications
Modified residuei1202 – 12021Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1242 – 12421Phosphotyrosine; by autocatalysis2 Publications
Modified residuei1258 – 12581Phosphotyrosine; by autocatalysis1 Publication
Modified residuei1284 – 12841Phosphotyrosine; by autocatalysis1 Publication

Post-translational modificationi

Isoform JM-A CYT-1 and isoform JM-A CYT-2 are processed by ADAM17. Proteolytic processing in response to ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation results in the production of 120 kDa soluble receptor forms and intermediate membrane-anchored 80 kDa fragments (m80HER4), which are further processed by a presenilin-dependent gamma-secretase to release a cytoplasmic intracellular domain (E4ICD; E4ICD1/s80Cyt1 or E4ICD2/s80Cyt2, depending on the isoform). Membrane-anchored 80 kDa fragments of the processed isoform JM-A CYT-1 are more readily degraded by the proteasome than fragments of isoform JM-A CYT-2, suggesting a prevalence of E4ICD2 over E4ICD1. Isoform JM-B CYT-1 and isoform JM-B CYT-2 lack the ADAM17 cleavage site and are not processed by ADAM17, precluding further processing by gamma-secretase.6 Publications
Autophosphorylated on tyrosine residues in response to ligand binding. Autophosphorylation occurs in trans, i.e. one subunit of the dimeric receptor phosphorylates tyrosine residues on the other subunit. Ligands trigger phosphorylation at specific tyrosine residues, thereby creating binding sites for scaffold proteins and effectors. Constitutively phosphorylated at a basal level when overexpressed in heterologous systems; ligand binding leads to increased phosphorylation. Phosphorylation at Tyr-1035 is important for interaction with STAT1. Phosphorylation at Tyr-1056 is important for interaction with PIK3R1. Phosphorylation at Tyr-1242 is important for interaction with SHC1. Phosphorylation at Tyr-1188 may also contribute to the interaction with SHC1. Isoform JM-A CYT-2 is constitutively phosphorylated on tyrosine residues in a ligand-independent manner. E4ICD2 but not E4ICD1 is phosphorylated on tyrosine residues.7 Publications
Ubiquitinated. During mitosis, the ERBB4 intracellular domain is ubiquitinated by the APC/C complex and targeted to proteasomal degradation. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are ubiquitinated by WWP1. The ERBB4 intracellular domain (E4ICD1) is ubiquitinated, and this involves NEDD4.2 Publications

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

MaxQBiQ15303.
PaxDbiQ15303.
PRIDEiQ15303.

PTM databases

PhosphoSiteiQ15303.

Miscellaneous databases

PMAP-CutDBQ15303.

Expressioni

Tissue specificityi

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.3 Publications

Gene expression databases

BgeeiQ15303.
CleanExiHS_ERBB4.
ExpressionAtlasiQ15303. baseline and differential.
GenevestigatoriQ15303.

Organism-specific databases

HPAiCAB000276.
CAB025522.
HPA012016.

Interactioni

Subunit structurei

Monomer in the absence of bound ligand. Homodimer or heterodimer with another ERBB family member upon ligand binding, thus forming heterotetramers. Interacts with EGFR and ERBB2. Interacts with CBFA2T3 (By similarity). Interacts with DLG2 (via its PDZ domain), DLG3 (via its PDZ domain), DLG4 (via its PDZ domain) and SNTB2 (via its PDZ domain). Interacts with MUC1. Interacts (via its PPxy motifs) with WWOX. Interacts (via the PPxY motif 3 of isoform JM-A CYT-2) with YAP1 (via the WW domain 1 of isoform 1). Interacts (isoform JM-A CYT-1 and isoform JM-B CYT-1) with WWP1. Interacts (via its intracellular domain) with TRIM28. Interacts (via the intracellular domains of both CYT-1 and CYT-2 isoforms) with KAP1; the interaction does not phosphorylate KAP1 but represses ERBB4-mediated transcriptional activity. Interacts with PRPU, DDX23, MATR3, RBM15, ILF3, KAP1, U5S1, U2SURP, ITCH, HNRPU, AP2A1, NULC, LEO1, WWP2, IGHG1, HXK1, GRB7 AND ARS2. Interacts (phosphorylated isoform JM-A CYT-1 and isoform JM-B CYT-1) with PIK3R1. Interacts with SHC1. Interacts with GRB2. Interacts (soluble intracellular domain) with STAT5A. Interacts (soluble intracellular domain) with BCL2. Interacts (phosphorylated) with STAT1.By similarity29 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
ABL2P426844EBI-80371,EBI-1102694
DLG4P783526EBI-80371,EBI-80389
EGFRP005332EBI-80371,EBI-297353
ERBB2P046262EBI-80371,EBI-641062
ERBB3P218604EBI-80371,EBI-720706
HSP90AB1P082382EBI-80371,EBI-352572
SHC1P293532EBI-80371,EBI-78835

Protein-protein interaction databases

BioGridi108378. 46 interactions.
DIPiDIP-29650N.
IntActiQ15303. 24 interactions.
MINTiMINT-125091.
STRINGi9606.ENSP00000342235.

Structurei

Secondary structure

1
1308
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Beta strandi28 – 303
Beta strandi38 – 414
Helixi42 – 5312
Beta strandi57 – 615
Beta strandi63 – 675
Helixi75 – 795
Beta strandi82 – 854
Beta strandi87 – 915
Beta strandi95 – 984
Turni112 – 1143
Beta strandi115 – 1206
Beta strandi125 – 1284
Beta strandi133 – 1353
Beta strandi144 – 1507
Helixi158 – 1603
Helixi163 – 1653
Helixi173 – 1753
Beta strandi176 – 1783
Turni191 – 1933
Beta strandi197 – 2015
Helixi202 – 2043
Beta strandi221 – 2255
Helixi226 – 2283
Beta strandi234 – 2429
Beta strandi245 – 25410
Beta strandi257 – 2615
Beta strandi265 – 2695
Turni270 – 2734
Beta strandi274 – 2774
Beta strandi283 – 2853
Beta strandi288 – 2925
Beta strandi298 – 3003
Beta strandi303 – 3075
Beta strandi312 – 3176
Beta strandi320 – 3256
Beta strandi327 – 3293
Beta strandi333 – 3353
Helixi340 – 3423
Turni350 – 3523
Helixi353 – 3564
Beta strandi360 – 3645
Beta strandi366 – 3683
Helixi370 – 3745
Helixi377 – 3793
Helixi386 – 3949
Beta strandi397 – 4004
Beta strandi402 – 4054
Helixi415 – 4173
Beta strandi432 – 4387
Beta strandi455 – 4617
Helixi469 – 4713
Helixi474 – 4763
Beta strandi479 – 4824
Beta strandi485 – 4873
Beta strandi489 – 4913
Helixi493 – 4975
Turni498 – 5003
Beta strandi512 – 5165
Beta strandi519 – 52810
Beta strandi531 – 5344
Beta strandi537 – 5437
Beta strandi545 – 5484
Beta strandi551 – 5544
Beta strandi568 – 5736
Beta strandi576 – 58510
Beta strandi588 – 5925
Beta strandi595 – 60814
Beta strandi612 – 6165
Beta strandi625 – 6295
Helixi651 – 67626
Helixi715 – 7173
Beta strandi718 – 72912
Beta strandi731 – 7377
Beta strandi740 – 7434
Beta strandi746 – 7527
Helixi762 – 77312
Beta strandi778 – 7803
Beta strandi783 – 7875
Beta strandi789 – 7913
Beta strandi793 – 7975
Helixi804 – 8107
Helixi812 – 8143
Helixi817 – 83620
Helixi846 – 8483
Beta strandi849 – 8535
Beta strandi856 – 8594
Helixi864 – 8696
Helixi884 – 8863
Helixi889 – 8935
Helixi899 – 91416
Turni920 – 9234
Turni926 – 9283
Helixi929 – 9346
Helixi947 – 9559
Helixi961 – 9633
Helixi967 – 97711
Helixi981 – 9833

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
2AHXX-ray2.40A/B26-641[»]
2L2TNMR-A/B642-685[»]
2LCXNMR-A/B642-685[»]
2R4BX-ray2.40A/B690-999[»]
3BBTX-ray2.80B/D702-1029[»]
3BBWX-ray4.00A/B702-1029[»]
3BCEX-ray2.50A/B/C702-1029[»]
3U2PX-ray2.57A26-522[»]
3U7UX-ray3.03A/B/C/D/E/F26-640[»]
3U9UX-ray3.42E/F26-650[»]
ProteinModelPortaliQ15303.
SMRiQ15303. Positions 26-639, 642-1074.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15303.

Topological domain

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini26 – 651626ExtracellularSequence AnalysisAdd
BLAST
Topological domaini676 – 1308633CytoplasmicSequence AnalysisAdd
BLAST

Transmembrane

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Transmembranei652 – 67524HelicalSequence AnalysisAdd
BLAST

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini718 – 985268Protein kinasePROSITE-ProRule annotationAdd
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi676 – 6849Nuclear localization signal
Motifi1032 – 10354PPxY motif 1
Motifi1053 – 10564PPxY motif 2
Motifi1298 – 13014PPxY motif 3
Motifi1306 – 13083PDZ-binding

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi186 – 334149Cys-richAdd
BLAST
Compositional biasi496 – 633138Cys-richAdd
BLAST

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00760000118799.
HOGENOMiHOG000230982.
HOVERGENiHBG000490.
InParanoidiQ15303.
KOiK05085.
OMAiRTRIDSN.
OrthoDBiEOG7V49XM.
PhylomeDBiQ15303.
TreeFamiTF106002.

Family and domain databases

Gene3Di3.80.20.20. 2 hits.
InterProiIPR000494. EGF_rcpt_L.
IPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_N_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016245. Tyr_kinase_EGF/ERB/XmrK_rcpt.
[Graphical view]
PfamiPF00757. Furin-like. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
[Graphical view]
PIRSFiPIRSF000619. TyrPK_EGF-R. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00261. FU. 5 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 2 hits.
PROSITEiPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 4 isoformsi produced by alternative splicing. Align

Isoform JM-A CYT-1 (identifier: Q15303) [UniParc]FASTAAdd to Basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR
60 70 80 90 100
KYYENCEVVM GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE
110 120 130 140 150
NLRIIRGTKL YEDRYALAIF LNYRKDGNFG LQELGLKNLT EILNGGVYVD
160 170 180 190 200
QNKFLCYADT IHWQDIVRNP WPSNLTLVST NGSSGCGRCH KSCTGRCWGP
210 220 230 240 250
TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG PKDTDCFACM
260 270 280 290 300
NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD
310 320 330 340 350
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS
360 370 380 390 400
SNIDKFINCT KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG
410 420 430 440 450
FLNIQSWPPN MTDFSVFSNL VTIGGRVLYS GLSLLILKQQ GITSLQFQSL
460 470 480 490 500
KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RKAENCTAEG
510 520 530 540 550
MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD GEFREFENGS
560 570 580 590 600
ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA
610 620 630 640 650
NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART
660 670 680 690 700
PLIAAGVIGG LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP
710 720 730 740 750
SGTAPNQAQL RILKETELKR VKVLGSGAFG TVYKGIWVPE GETVKIPVAI
760 770 780 790 800
KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP TIQLVTQLMP
810 820 830 840 850
HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV HRDLAARNVL
860 870 880 890 900
VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ
910 920 930 940 950
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY
960 970 980 990 1000
MVMVKCWMID ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND
1010 1020 1030 1040 1050
SKFFQNLLDE EDLEDMMDAE EYLVPQAFNI PPPIYTSRAR IDSNRSEIGH
1060 1070 1080 1090 1100
SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP YRAPTSTIPE APVAQGATAE
1110 1120 1130 1140 1150
IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS PRGELDEEGY
1160 1170 1180 1190 1200
MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED
1210 1220 1230 1240 1250
EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR
1260 1270 1280 1290 1300
STLQHPDYLQ EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP

YRHRNTVV

Note: Proteolytical processing generates E4ICD1 (s80Cyt1).

Length:1,308
Mass (Da):146,808
Last modified:November 1, 1996 - v1
Checksum:i5E4AE80985D88761
GO
Isoform JM-B CYT-1 (identifier: Q15303-2) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     626-648: NGPTSHDCIYYPWTGHSTLPQHA → IGSSIEDCIGLMD

Show »
Length:1,298
Mass (Da):145,578
Checksum:i346C1288AD041961
GO
Isoform JM-A CYT-2 (identifier: Q15303-3) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     1046-1061: Missing.

Note: Proteolytical processing generates E4ICD2 (s80Cyt2).

Show »
Length:1,292
Mass (Da):145,198
Checksum:i60C0DFD446C7FA89
GO
Isoform JM-B CYT-2 (identifier: Q15303-4) [UniParc]FASTAAdd to Basket

The sequence of this isoform differs from the canonical sequence as follows:
     626-648: NGPTSHDCIYYPWTGHSTLPQHA → IGSSIEDCIGLMD
     1046-1061: Missing.

Show »
Length:1,282
Mass (Da):143,968
Checksum:i68F27777BC9E2F74
GO

Natural variant

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Natural varianti140 – 1401T → I in a colorectal adenocarcinoma sample; somatic mutation. 1 Publication
VAR_042113
Natural varianti303 – 3031S → Y in a lung squamous cell carcinoma sample; somatic mutation. 1 Publication
VAR_042114
Natural varianti927 – 9271R → Q in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
VAR_070810
Natural varianti1275 – 12751R → W in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 Publication
VAR_070811

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei626 – 64823NGPTS…LPQHA → IGSSIEDCIGLMD in isoform JM-B CYT-1 and isoform JM-B CYT-2. 2 PublicationsVSP_002895Add
BLAST
Alternative sequencei1046 – 106116Missing in isoform JM-A CYT-2 and isoform JM-B CYT-2. 2 PublicationsVSP_022148Add
BLAST

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
L07868 mRNA. Translation: AAB59446.1.
BC112199 mRNA. Translation: AAI12200.1.
BC143741 mRNA. Translation: AAI43742.1.
BC143747 mRNA. Translation: AAI43748.1.
BC143749 mRNA. Translation: AAI43750.1.
AB209697 mRNA. Translation: BAD92934.1.
CCDSiCCDS2394.1. [Q15303-1]
CCDS42811.1. [Q15303-3]
PIRiA47253.
RefSeqiNP_001036064.1. NM_001042599.1. [Q15303-3]
NP_005226.1. NM_005235.2. [Q15303-1]
XP_005246433.1. XM_005246376.1. [Q15303-2]
XP_005246434.1. XM_005246377.1. [Q15303-4]
UniGeneiHs.390729.

Genome annotation databases

EnsembliENST00000342788; ENSP00000342235; ENSG00000178568. [Q15303-1]
ENST00000436443; ENSP00000403204; ENSG00000178568. [Q15303-3]
GeneIDi2066.
KEGGihsa:2066.
UCSCiuc002veg.1. human. [Q15303-1]
uc002veh.1. human. [Q15303-3]
uc010zji.1. human. [Q15303-2]
uc010zjj.1. human. [Q15303-4]

Polymorphism databases

DMDMi3913590.

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
L07868 mRNA. Translation: AAB59446.1 .
BC112199 mRNA. Translation: AAI12200.1 .
BC143741 mRNA. Translation: AAI43742.1 .
BC143747 mRNA. Translation: AAI43748.1 .
BC143749 mRNA. Translation: AAI43750.1 .
AB209697 mRNA. Translation: BAD92934.1 .
CCDSi CCDS2394.1. [Q15303-1 ]
CCDS42811.1. [Q15303-3 ]
PIRi A47253.
RefSeqi NP_001036064.1. NM_001042599.1. [Q15303-3 ]
NP_005226.1. NM_005235.2. [Q15303-1 ]
XP_005246433.1. XM_005246376.1. [Q15303-2 ]
XP_005246434.1. XM_005246377.1. [Q15303-4 ]
UniGenei Hs.390729.

3D structure databases

Select the link destinations:
PDBe
RCSB PDB
PDBj
Links Updated
Entry Method Resolution (Å) Chain Positions PDBsum
2AHX X-ray 2.40 A/B 26-641 [» ]
2L2T NMR - A/B 642-685 [» ]
2LCX NMR - A/B 642-685 [» ]
2R4B X-ray 2.40 A/B 690-999 [» ]
3BBT X-ray 2.80 B/D 702-1029 [» ]
3BBW X-ray 4.00 A/B 702-1029 [» ]
3BCE X-ray 2.50 A/B/C 702-1029 [» ]
3U2P X-ray 2.57 A 26-522 [» ]
3U7U X-ray 3.03 A/B/C/D/E/F 26-640 [» ]
3U9U X-ray 3.42 E/F 26-650 [» ]
ProteinModelPortali Q15303.
SMRi Q15303. Positions 26-639, 642-1074.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

BioGridi 108378. 46 interactions.
DIPi DIP-29650N.
IntActi Q15303. 24 interactions.
MINTi MINT-125091.
STRINGi 9606.ENSP00000342235.

Chemistry

BindingDBi Q15303.
ChEMBLi CHEMBL2363049.
DrugBanki DB08916. Afatinib.
GuidetoPHARMACOLOGYi 1799.

PTM databases

PhosphoSitei Q15303.

Polymorphism databases

DMDMi 3913590.

Proteomic databases

MaxQBi Q15303.
PaxDbi Q15303.
PRIDEi Q15303.

Protocols and materials databases

DNASUi 2066.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENST00000342788 ; ENSP00000342235 ; ENSG00000178568 . [Q15303-1 ]
ENST00000436443 ; ENSP00000403204 ; ENSG00000178568 . [Q15303-3 ]
GeneIDi 2066.
KEGGi hsa:2066.
UCSCi uc002veg.1. human. [Q15303-1 ]
uc002veh.1. human. [Q15303-3 ]
uc010zji.1. human. [Q15303-2 ]
uc010zjj.1. human. [Q15303-4 ]

Organism-specific databases

CTDi 2066.
GeneCardsi GC02M212210.
HGNCi HGNC:3432. ERBB4.
HPAi CAB000276.
CAB025522.
HPA012016.
MIMi 600543. gene.
615515. phenotype.
neXtProti NX_Q15303.
Orphaneti 803. Amyotrophic lateral sclerosis.
PharmGKBi PA27847.
GenAtlasi Search...

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00760000118799.
HOGENOMi HOG000230982.
HOVERGENi HBG000490.
InParanoidi Q15303.
KOi K05085.
OMAi RTRIDSN.
OrthoDBi EOG7V49XM.
PhylomeDBi Q15303.
TreeFami TF106002.

Enzyme and pathway databases

BRENDAi 2.7.10.1. 2681.
Reactomei REACT_115596. Signaling by ERBB4.
REACT_115755. Signaling by ERBB2.
REACT_115828. Downregulation of ERBB4 signaling.
REACT_115854. GRB2 events in ERBB2 signaling.
REACT_115961. PI3K events in ERBB4 signaling.
REACT_115993. SHC1 events in ERBB2 signaling.
REACT_116005. SHC1 events in ERBB4 signaling.
REACT_116008. PI3K events in ERBB2 signaling.
REACT_116022. Nuclear signaling by ERBB4.
REACT_147727. Constitutive PI3K/AKT Signaling in Cancer.
REACT_75829. PIP3 activates AKT signaling.
SignaLinki Q15303.

Miscellaneous databases

ChiTaRSi ERBB4. human.
EvolutionaryTracei Q15303.
GeneWikii ERBB4.
GenomeRNAii 2066.
NextBioi 8397.
PMAP-CutDB Q15303.
PROi Q15303.
SOURCEi Search...

Gene expression databases

Bgeei Q15303.
CleanExi HS_ERBB4.
ExpressionAtlasi Q15303. baseline and differential.
Genevestigatori Q15303.

Family and domain databases

Gene3Di 3.80.20.20. 2 hits.
InterProi IPR000494. EGF_rcpt_L.
IPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR009030. Growth_fac_rcpt_N_dom.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016245. Tyr_kinase_EGF/ERB/XmrK_rcpt.
[Graphical view ]
Pfami PF00757. Furin-like. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
[Graphical view ]
PIRSFi PIRSF000619. TyrPK_EGF-R. 1 hit.
PRINTSi PR00109. TYRKINASE.
SMARTi SM00261. FU. 5 hits.
SM00219. TyrKc. 1 hit.
[Graphical view ]
SUPFAMi SSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 2 hits.
PROSITEi PS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  1. "Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family."
    Plowman G.D., Culouscou J.-M., Whitney G.S., Green J.M., Carlton G.W., Foy L., Neubauer M.G., Shoyab M.
    Proc. Natl. Acad. Sci. U.S.A. 90:1746-1750(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM JM-A CYT-1), FUNCTION AS CELL SURFACE RECEPTOR, AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY.
    Tissue: Mammary carcinoma.
  2. "A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific tissue distribution and differential processing in response to phorbol ester."
    Elenius K., Corfas G., Paul S., Choi C.J., Rio C., Plowman G.D., Klagsbrun M.
    J. Biol. Chem. 272:26761-26768(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS JM-A CYT-1 AND JM-B CYT-1), TISSUE SPECIFICITY, FUNCTION AS CELL SURFACE RECEPTOR FOR NRG1 AND BTC, SUBCELLULAR LOCATION, AUTOPHOSPHORYLATION, PROTEOLYTIC PROCESSING.
    Tissue: Fetal brain.
  3. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
    The MGC Project Team
    Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS JM-A CYT-1; JM-B CYT-1; JM-A CYT-2 AND JM-B CYT-2).
    Tissue: Brain.
  4. Totoki Y., Toyoda A., Takeda T., Sakaki Y., Tanaka A., Yokoyama S., Ohara O., Nagase T., Kikuno R.F.
    Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 401-1308 (ISOFORM JM-A CYT-2).
    Tissue: Brain.
  5. "Characterization of a breast cancer cell differentiation factor that specifically activates the HER4/p180erbB4 receptor."
    Culouscou J.-M., Plowman G.D., Carlton G.W., Green J.M., Shoyab M.
    J. Biol. Chem. 268:18407-18410(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NRG1, AUTOPHOSPHORYLATION.
  6. "Heregulin induces tyrosine phosphorylation of HER4/p180erbB4."
    Plowman G.D., Green J.M., Culouscou J.M., Carlton G.W., Rothwell V.M., Buckley S.
    Nature 366:473-475(1993) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NRG1, AUTOPHOSPHORYLATION.
  7. "HER4-mediated biological and biochemical properties in NIH 3T3 cells. Evidence for HER1-HER4 heterodimers."
    Cohen B.D., Green J.M., Foy L., Fell H.P.
    J. Biol. Chem. 271:4813-4818(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS NRG1 RECEPTOR IN REGULATION OF CELL PROLIFERATION, CATALYTIC ACTIVITY, ENZYME REGULATION, AUTOPHOSPHORYLATION, PHOSPHORYLATION AT TYR-1056; TYR-1188 AND TYR-1242, INTERACTION WITH EGFR; SHC1 AND PIK3R1.
  8. "Betacellulin activates the epidermal growth factor receptor and erbB-4, and induces cellular response patterns distinct from those stimulated by epidermal growth factor or neuregulin-beta."
    Riese D.J. II, Bermingham Y., van Raaij T.M., Buckley S., Plowman G.D., Stern D.F.
    Oncogene 12:345-353(1996) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH BTC, AUTOPHOSPHORYLATION.
  9. "Activation of HER4 by heparin-binding EGF-like growth factor stimulates chemotaxis but not proliferation."
    Elenius K., Paul S., Allison G., Sun J., Klagsbrun M.
    EMBO J. 16:1268-1278(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS HBEGF RECEPTOR; IN CELL MIGRATION; CELL PROLIFERATION AND IN ACTIVATION OF PIK3R1, INTERACTION WITH HBEGF AND PIK3R1, AUTOPHOSPHORYLATION.
  10. "Neuregulin-2, a new ligand of ErbB3/ErbB4-receptor tyrosine kinases."
    Carraway K.L. III, Weber J.L., Unger M.J., Ledesma J., Yu N., Gassmann M., Lai C.
    Nature 387:512-516(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NRG2, FUNCTION AS NRG2 RECEPTOR, PHOSPHORYLATION.
  11. "Epiregulin binds to epidermal growth factor receptor and ErbB-4 and induces tyrosine phosphorylation of epidermal growth factor receptor, ErbB-2, ErbB-3 and ErbB-4."
    Komurasaki T., Toyoda H., Uchida D., Morimoto S.
    Oncogene 15:2841-2848(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH EREG, AUTOPHOSPHORYLATION.
  12. "Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4."
    Zhang D., Sliwkowski M.X., Mark M., Frantz G., Akita R., Sun Y., Hillan K., Crowley C., Brush J., Godowski P.J.
    Proc. Natl. Acad. Sci. U.S.A. 94:9562-9567(1997) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NRG3, AUTOPHOSPHORYLATION.
  13. "Analysis of Grb7 recruitment by heregulin-activated erbB receptors reveals a novel target selectivity for erbB3."
    Fiddes R.J., Campbell D.H., Janes P.W., Sivertsen S.P., Sasaki H., Wallasch C., Daly R.J.
    J. Biol. Chem. 273:7717-7724(1998) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH GRB7.
  14. "ErbB receptor-induced activation of stat transcription factors is mediated by Src tyrosine kinases."
    Olayioye M.A., Beuvink I., Horsch K., Daly J.M., Hynes N.E.
    J. Biol. Chem. 274:17209-17218(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ERBB2, FUNCTION IN ACTIVATION OF STAT5A.
  15. "Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase."
    Elenius K., Choi C.J., Paul S., Santiestevan E., Nishi E., Klagsbrun M.
    Oncogene 18:2607-2615(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: ALTERNATIVE SPLICING, FUNCTION IN PHOSPHORYLATION AND ACTIVATION OF PIK3R1, INTERACTION WITH NRG1 AND PIKR3R1, AUTOPHOSPHORYLATION, TISSUE SPECIFICITY.
  16. "Neuregulin-4: a novel growth factor that acts through the ErbB-4 receptor tyrosine kinase."
    Harari D., Tzahar E., Romano J., Shelly M., Pierce J.H., Andrews G.C., Yarden Y.
    Oncogene 18:2681-2689(1999) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS NRG4 RECEPTOR IN ACTIVATION OF MAPK1/ERK2 AND MAPK3/ERK1 AND IN CELL PROLIFERATION, INTERACTION WITH NRG4, SUBCELLULAR LOCATION.
  17. "A natural ErbB4 isoform that does not activate phosphoinositide 3-kinase mediates proliferation but not survival or chemotaxis."
    Kainulainen V., Sundvall M., Maatta J.A., Santiestevan E., Klagsbrun M., Elenius K.
    J. Biol. Chem. 275:8641-8649(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS NRG1 RECEPTOR IN CELL PROLIFERATION; MIGRATION; SURVIVAL AND IN PHOSPHORYLATION OF SHC1; ACTIVATION OF MAPK1/ERK2 AND MAPK3/ERK1, ALTERNATIVE SPLICING.
  18. "Tumor necrosis factor-alpha-converting enzyme is required for cleavage of erbB4/HER4."
    Rio C., Buxbaum J.D., Peschon J.J., Corfas G.
    J. Biol. Chem. 275:10379-10387(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: PROTEOLYTIC PROCESSING.
  19. "Ligand discrimination in signaling through an ErbB4 receptor homodimer."
    Sweeney C., Lai C., Riese D.J. II, Diamonti A.J., Cantley L.C., Carraway K.L. III
    J. Biol. Chem. 275:19803-19807(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN ACTIVATION OF AKT1; MAPK1/ERK2 AND MAPK3/ERK1, INTERACTION WITH PIK3R1; GRB2; SHC1; BTC; NRG1; NRG2 AND NRG3, LIGAND-SPECIFIC AUTOPHOSPHORYLATION.
  20. "The neuregulin receptor ErbB-4 interacts with PDZ-containing proteins at neuronal synapses."
    Garcia R.A., Vasudevan K., Buonanno A.
    Proc. Natl. Acad. Sci. U.S.A. 97:3596-3601(2000) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH DLG2; DLG3; DLG4 AND SNTB2.
  21. "BIBX1382BS, but not AG1478 or PD153035, inhibits the ErbB kinases at different concentrations in intact cells."
    Egeblad M., Mortensen O.H., van Kempen L.C., Jaattela M.
    Biochem. Biophys. Res. Commun. 281:25-31(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION AS NRG1 RECEPTOR AND IN ACTIVATION OF MAP KINASES, AUTOPHOSPHORYLATION, ENZYME REGULATION.
  22. "Her4 mediates ligand-dependent antiproliferative and differentiation responses in human breast cancer cells."
    Sartor C.I., Zhou H., Kozlowska E., Guttridge K., Kawata E., Caskey L., Harrelson J., Hynes N., Ethier S., Calvo B., Earp H.S. III
    Mol. Cell. Biol. 21:4265-4275(2001) [PubMed] [Europe PMC] [Abstract]
    Cited for: MUTAGENESIS OF LYS-751, FUNCTION IN PROMOTING CELL DIFFERENTIATION AND INHIBITING CELL PROLIFERATION.
  23. "WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus."
    Komuro A., Nagai M., Navin N.E., Sudol M.
    J. Biol. Chem. 278:33334-33341(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, INTERACTION WITH YAP1, MUTAGENESIS OF TYR-1301.
  24. "Heregulin targets gamma-catenin to the nucleolus by a mechanism dependent on the DF3/MUC1 oncoprotein."
    Li Y., Yu W.-H., Ren J., Chen W., Huang L., Kharbanda S., Loda M., Kufe D.
    Mol. Cancer Res. 1:765-775(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH MUC1.
  25. "The ERBB4/HER4 receptor tyrosine kinase regulates gene expression by functioning as a STAT5A nuclear chaperone."
    Williams C.C., Allison J.G., Vidal G.A., Burow M.E., Beckman B.S., Marrero L., Jones F.E.
    J. Cell Biol. 167:469-478(2004) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH STAT5A, SUBCELLULAR LOCATION, FUNCTION IN NUCLEAR LOCALIZATION OF STAT5A; DNA-BINDING, MUTAGENESIS OF 681-LYS--ARG-684.
  26. "WW domain-containing proteins, WWOX and YAP, compete for interaction with ErbB-4 and modulate its transcriptional function."
    Aqeilan R.I., Donati V., Palamarchuk A., Trapasso F., Kaou M., Pekarsky Y., Sudol M., Croce C.M.
    Cancer Res. 65:6764-6772(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH WWOX, DOMAIN, MUTAGENESIS OF TYR-1035 AND TYR-1301.
  27. "Presenilin-dependent gamma-secretase processing regulates multiple ERBB4/HER4 activities."
    Vidal G.A., Naresh A., Marrero L., Jones F.E.
    J. Biol. Chem. 280:19777-19783(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, PROTEOLYTIC PROCESSING, MUTAGENESIS OF VAL-675.
  28. "The ERBB4/HER4 intracellular domain 4ICD is a BH3-only protein promoting apoptosis of breast cancer cells."
    Naresh A., Long W., Vidal G.A., Wimley W.C., Marrero L., Sartor C.I., Tovey S., Cooke T.G., Bartlett J.M., Jones F.E.
    Cancer Res. 66:6412-6420(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN PROMOTING APOPTOSIS, SUBCELLULAR LOCATION, INTERACTION WITH BCL2.
  29. "ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression."
    Linggi B., Carpenter G.
    J. Biol. Chem. 281:25373-25380(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH CBFA2T3.
  30. "Proteolytic cleavage and phosphorylation of a tumor-associated ErbB4 isoform promote ligand-independent survival and cancer cell growth."
    Maatta J.A., Sundvall M., Junttila T.T., Peri L., Laine V.J., Isola J., Egeblad M., Elenius K.
    Mol. Biol. Cell 17:67-79(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, PHOSPHORYLATION, SUBCELLULAR LOCATION.
  31. "The intracellular domain of ErbB4 induces differentiation of mammary epithelial cells."
    Muraoka-Cook R.S., Sandahl M., Husted C., Hunter D., Miraglia L., Feng S.M., Elenius K., Earp H.S. III
    Mol. Biol. Cell 17:4118-4129(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN DIFFERENTIATION OF MAMMARY EPITHELIUM, PROTEOLYTIC PROCESSING, AUTOPHOSPHORYLATION, SUBCELLULAR LOCATION, INTERACTION WITH STAT5A.
  32. "Phosphorylation of ErbB4 on tyrosine 1056 is critical for ErbB4 coupling to inhibition of colony formation by human mammary cell lines."
    Pitfield S.E., Bryant I., Penington D.J., Park G., Riese D.J. II
    Oncol. Res. 16:179-193(2006) [PubMed] [Europe PMC] [Abstract]
    Cited for: MUTAGENESIS OF GLN-646, PHOSPHORYLATION AT TYR-1056.
  33. "HER4 D-box sequences regulate mitotic progression and degradation of the nuclear HER4 cleavage product s80HER4."
    Strunk K.E., Husted C., Miraglia L.C., Sandahl M., Rearick W.A., Hunter D.M., Earp H.S. III, Muraoka-Cook R.S.
    Cancer Res. 67:6582-6590(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION OF ERBB4 INTRACELLULAR DOMAIN, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, UBIQUITINATION OF ERBB4 INTRACELLULAR DOMAIN, MUTAGENESIS OF VAL-675; LYS-751; ARG-992; LEU-995 AND ASP-1000.
  34. "Neuregulin-1 only induces trans-phosphorylation between ErbB receptor heterodimer partners."
    Li Z., Mei Y., Liu X., Zhou M.
    Cell. Signal. 19:466-471(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH ERBB2, MUTAGENESIS OF ASP-843, AUTOPHOSPHORYLATION IN TRANS.
  35. "Differential nuclear localization and kinase activity of alternative ErbB4 intracellular domains."
    Sundvall M., Peri L., Maatta J.A., Tvorogov D., Paatero I., Savisalo M., Silvennoinen O., Yarden Y., Elenius K.
    Oncogene 26:6905-6914(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION OF E4ICD, PHOSPHORYLATION, SUBCELLULAR LOCATION OF E4ICD, MUTAGENESIS OF LYS-751.
  36. "System-wide investigation of ErbB4 reveals 19 sites of Tyr phosphorylation that are unusually selective in their recruitment properties."
    Kaushansky A., Gordus A., Budnik B.A., Lane W.S., Rush J., MacBeath G.
    Chem. Biol. 15:808-817(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: PHOSPHORYLATION AT TYR-875; TYR-1035; TYR-1056; TYR-1150; TYR-1162; TYR-1188; TYR-1202; TYR-1242; TYR-1258 AND TYR-1284, INTERACTION WITH PIK3R1 AND STAT1, IDENTIFICATION BY MASS SPECTROMETRY.
  37. "Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells."
    Zeng F., Xu J., Harris R.C.
    FASEB J. 23:1935-1945(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH NEDD4, SUBCELLULAR LOCATION, UBIQUITINATION OF E4ICD1.
  38. "Somatic mutations of ErbB4: selective loss-of-function phenotype affecting signal transduction pathways in cancer."
    Tvorogov D., Sundvall M., Kurppa K., Hollmen M., Repo S., Johnson M.S., Elenius K.
    J. Biol. Chem. 284:5582-5591(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION IN ACTIVATION OF SIGNALING PATHWAYS, INTERACTION WITH ERBB2, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, PHOSPHORYLATION BY ERBB2, ENZYME REGULATION, MUTAGENESIS OF VAL-721; ALA-773; ARG-782; GLU-810; PRO-854; ASP-861; GLU-872 AND THR-926.
  39. "WW domain containing E3 ubiquitin protein ligase 1 targets the full-length ErbB4 for ubiquitin-mediated degradation in breast cancer."
    Li Y., Zhou Z., Alimandi M., Chen C.
    Oncogene 28:2948-2958(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH WWP1, MUTAGENESIS OF TYR-1056 AND TYR-1301.
  40. "Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways."
    Gilmore-Hebert M., Ramabhadran R., Stern D.F.
    Mol. Cancer Res. 8:1388-1398(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: INTERACTION WITH TXNL4A; DDX23; MATR3; RBM15; ILF3; TRIM28; U5S1; U2SURP; ITCH; HNRPU; AP2A1; NULC; LEO1; WWP2; MDM2; HXK1 AND ARS2, FUNCTION, SUBCELLULAR LOCATION, IDENTIFICATION BY MASS SPECTROMETRY.
  41. "Small tyrosine kinase inhibitors interrupt EGFR signaling by interacting with erbB3 and erbB4 in glioblastoma cell lines."
    Carrasco-Garcia E., Saceda M., Grasso S., Rocamora-Reverte L., Conde M., Gomez-Martinez A., Garcia-Morales P., Ferragut J.A., Martinez-Lacaci I.
    Exp. Cell Res. 317:1476-1489(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: ENZYME REGULATION.
  42. "ErbB4 signaling during breast and neural development: novel genetic models reveal unique ErbB4 activities."
    Jones F.E., Golding J.P., Gassmann M.
    Cell Cycle 2:555-559(2003) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON ROLE IN BREAST AND NEURAL DEVELOPMENT.
  43. "The diverse signaling network of EGFR, HER2, HER3 and HER4 tyrosine kinase receptors and the consequences for therapeutic approaches."
    Zaczek A., Brandt B., Bielawski K.P.
    Histol. Histopathol. 20:1005-1015(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW.
  44. "ErbB4/HER4: role in mammary gland development, differentiation and growth inhibition."
    Muraoka-Cook R.S., Feng S.M., Strunk K.E., Earp H.S. III
    J. Mammary Gland Biol. Neoplasia 13:235-246(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON ROLE IN MAMMARY GLAND DEVELOPMENT.
  45. "HER4 intracellular domain (4ICD) activity in the developing mammary gland and breast cancer."
    Jones F.E.
    J. Mammary Gland Biol. Neoplasia 13:247-258(2008) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON ROLE OF THE ERBB4 INTRACELLULAR DOMAIN.
  46. Cited for: REVIEW ON LIGAND SPECIFICITY AND SIGNALING.
  47. "Neuregulin-1/ErbB signaling and chronic heart failure."
    Xu Y., Li X., Liu X., Zhou M.
    Adv. Pharmacol. 59:31-51(2010) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON ROLE IN NRG1 SIGNALING AND CARDIOVASCULAR HEALTH.
  48. "Function of ERBB4 is determined by alternative splicing."
    Veikkolainen V., Vaparanta K., Halkilahti K., Iljin K., Sundvall M., Elenius K.
    Cell Cycle 10:2647-2657(2011) [PubMed] [Europe PMC] [Abstract]
    Cited for: REVIEW ON ALTERNATIVE SPLICING AND PROTEOLYTIC PROCESSING; TISSUE SPECIFICITY; SIGNALING AND ROLE IN DISEASE.
  49. "The extracellular region of ErbB4 adopts a tethered conformation in the absence of ligand."
    Bouyain S., Longo P.A., Li S., Ferguson K.M., Leahy D.J.
    Proc. Natl. Acad. Sci. U.S.A. 102:15024-15029(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 26-641, DISULFIDE BONDS, GLYCOSYLATION AT ASN-138; ASN-174; ASN-253; ASN-358; ASN-410; ASN-473; ASN-495 AND ASN-576.
  50. Cited for: X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 690-999 IN COMPLEX WITH INHIBITOR, CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION, MUTAGENESIS OF LEU-710; MET-766; LEU-864 AND ILE-947.
  51. Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 702-1029 OF APOPROTEIN AND IN COMPLEX WITH LAPATINIB, CATALYTIC ACTIVITY, ENZYME REGULATION, AUTOPHOSPHORYLATION, SUBUNIT.
  52. "Patterns of somatic mutation in human cancer genomes."
    Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.
    , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
    Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS [LARGE SCALE ANALYSIS] ILE-140 AND TYR-303.
  53. "ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19."
    Takahashi Y., Fukuda Y., Yoshimura J., Toyoda A., Kurppa K., Moritoyo H., Belzil V.V., Dion P.A., Higasa K., Doi K., Ishiura H., Mitsui J., Date H., Ahsan B., Matsukawa T., Ichikawa Y., Moritoyo T., Ikoma M.
    , Hashimoto T., Kimura F., Murayama S., Onodera O., Nishizawa M., Yoshida M., Atsuta N., Sobue G., Fifita J.A., Williams K.L., Blair I.P., Nicholson G.A., Gonzalez-Perez P., Brown R.H. Jr., Nomoto M., Elenius K., Rouleau G.A., Fujiyama A., Morishita S., Goto J., Tsuji S., Nakamura R., Watanabe H., Izumi Y., Kaji R., Morita M., Ogaki K., Taniguchi A., Aiba I., Mizoguchi K., Okamoto K., Hasegawa K., Aoki M., Kawata A., Nakano I., Abe K., Oda M., Konagaya M., Imai T., Nakagawa M., Fujita T., Sasaki H., Nishizawa M.
    Am. J. Hum. Genet. 93:900-905(2013) [PubMed] [Europe PMC] [Abstract]
    Cited for: VARIANTS ALS19 GLN-927 AND TRP-1275, CHARACTERIZATION OF VARIANTS ASL19 GLN-927 AND TRP-1275.

Entry informationi

Entry nameiERBB4_HUMAN
AccessioniPrimary (citable) accession number: Q15303
Secondary accession number(s): B7ZLD7
, B7ZLE2, B7ZLE3, Q2M1W1, Q59EW4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: November 1, 1996
Last modified: October 29, 2014
This is version 169 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3