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Protein

Receptor tyrosine-protein kinase erbB-4

Gene

ERBB4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: 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.PROSITE-ProRule annotation4 Publications

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)DescriptionActionsGraphical viewLength
Binding sitei751ATPPROSITE-ProRule annotation1
Active sitei843Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi724 – 732ATPPROSITE-ProRule annotation9
Nucleotide bindingi797 – 799ATPPROSITE-ProRule annotation3
Nucleotide bindingi843 – 848ATPPROSITE-ProRule annotation6

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • epidermal growth factor receptor binding Source: UniProtKB
  • phosphatidylinositol-4,5-bisphosphate 3-kinase activity Source: Reactome
  • protein homodimerization activity Source: UniProtKB
  • protein tyrosine kinase activity Source: UniProtKB
  • Ras guanyl-nucleotide exchange factor activity Source: Reactome
  • receptor signaling protein tyrosine kinase activity Source: InterPro
  • transcription regulatory region DNA binding Source: UniProtKB
  • transmembrane receptor protein tyrosine kinase activity Source: UniProtKB

GO - Biological processi

  • cardiac muscle tissue regeneration Source: UniProtKB
  • cell fate commitment Source: Ensembl
  • cell migration Source: UniProtKB
  • cell proliferation Source: ProtInc
  • central nervous system morphogenesis Source: UniProtKB
  • embryonic pattern specification Source: UniProtKB
  • ERBB2 signaling pathway Source: Reactome
  • heart development Source: UniProtKB
  • lactation Source: UniProtKB
  • mammary gland alveolus development Source: UniProtKB
  • mammary gland epithelial cell differentiation Source: UniProtKB
  • MAPK cascade Source: Reactome
  • mitochondrial fragmentation involved in apoptotic process Source: UniProtKB
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of cell proliferation Source: UniProtKB
  • negative regulation of neuron migration Source: Ensembl
  • nervous system development Source: UniProtKB
  • neural crest cell migration Source: UniProtKB
  • olfactory bulb interneuron differentiation Source: UniProtKB
  • peptidyl-tyrosine autophosphorylation Source: Ensembl
  • peptidyl-tyrosine phosphorylation Source: UniProtKB
  • phosphatidylinositol-mediated signaling Source: Reactome
  • positive regulation of apoptotic process Source: Ensembl
  • positive regulation of cardiac muscle cell proliferation Source: UniProtKB
  • positive regulation of cell proliferation Source: UniProtKB
  • positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
  • positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
  • positive regulation of phosphatidylinositol 3-kinase signaling Source: Ensembl
  • positive regulation of protein localization to cell surface Source: Ensembl
  • positive regulation of protein phosphorylation Source: UniProtKB
  • positive regulation of STAT protein import into nucleus Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of tyrosine phosphorylation of Stat5 protein Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • regulation of cell migration Source: UniProtKB
  • regulation of cell motility Source: Reactome
  • regulation of phosphatidylinositol 3-kinase signaling Source: Reactome
  • signal transduction Source: UniProtKB
  • transcription, DNA-templated Source: UniProtKB-KW
  • 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

BioCyciZFISH:HS17081-MONOMER.
BRENDAi2.7.10.1. 2681.
ReactomeiR-HSA-1227986. Signaling by ERBB2.
R-HSA-1236394. Signaling by ERBB4.
R-HSA-1250196. SHC1 events in ERBB2 signaling.
R-HSA-1250342. PI3K events in ERBB4 signaling.
R-HSA-1250347. SHC1 events in ERBB4 signaling.
R-HSA-1251985. Nuclear signaling by ERBB4.
R-HSA-1253288. Downregulation of ERBB4 signaling.
R-HSA-1257604. PIP3 activates AKT signaling.
R-HSA-1963640. GRB2 events in ERBB2 signaling.
R-HSA-1963642. PI3K events in ERBB2 signaling.
R-HSA-2219530. Constitutive Signaling by Aberrant PI3K in Cancer.
R-HSA-5673001. RAF/MAP kinase cascade.
R-HSA-6785631. ERBB2 Regulates Cell Motility.
R-HSA-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-HSA-8847993. ERBB2 Activates PTK6 Signaling.
R-HSA-8863795. Downregulation of ERBB2 signaling.
SignaLinkiQ15303.
SIGNORiQ15303.

Protein family/group databases

TCDBi1.A.87.2.6. the mechanosensitive calcium channel (mca) family.

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
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

HGNCiHGNC:3432. ERBB4.

Subcellular locationi

ERBB4 intracellular domain :

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini26 – 651ExtracellularSequence analysisAdd BLAST626
Transmembranei652 – 675HelicalSequence analysisAdd BLAST24
Topological domaini676 – 1308CytoplasmicSequence analysisAdd BLAST633

GO - Cellular componenti

  • basolateral plasma membrane Source: BHF-UCL
  • cytosol Source: Reactome
  • extracellular region Source: Reactome
  • integral component of membrane Source: UniProtKB-KW
  • mitochondrial matrix Source: Reactome
  • mitochondrion Source: UniProtKB
  • nucleoplasm Source: Reactome
  • nucleus Source: UniProtKB
  • plasma membrane Source: Reactome
  • 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)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA 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.
See also OMIM:615515
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_070810927R → Q in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 PublicationCorresponds to variant rs397514262dbSNPEnsembl.1
Natural variantiVAR_0708111275R → W in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 PublicationCorresponds to variant rs397514263dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi646Q → C: Constitutively activated kinase. 1 Publication1
Mutagenesisi675V → A: Abolishes proteolytic processing and nuclear localization. 2 Publications1
Mutagenesisi681 – 684KKKR → EIMG: Abolishes nuclear localization of the ERBB4 intracellular domain. 1 Publication4
Mutagenesisi710L → N: Strongly reduced autophosphorylation. 1 Publication1
Mutagenesisi721V → I: No effect on kinase activity. 1 Publication1
Mutagenesisi751K → R: Abolishes kinase activity. Abolishes phosphorylation, proteolytic processing and nuclear localization. 3 Publications1
Mutagenesisi766M → R: Strongly reduced autophosphorylation. 1 Publication1
Mutagenesisi773A → S: No effect on kinase activity. 1 Publication1
Mutagenesisi782R → Q: No effect on kinase activity. 1 Publication1
Mutagenesisi810E → K: No effect on kinase activity. 1 Publication1
Mutagenesisi843D → N: Loss of kinase activity. 1 Publication1
Mutagenesisi854P → Q: No effect on kinase activity. 1 Publication1
Mutagenesisi861D → Y: Loss of kinase activity. 1 Publication1
Mutagenesisi864L → R: Strongly reduced autophosphorylation. 1 Publication1
Mutagenesisi872E → K: No effect on kinase activity. 1 Publication1
Mutagenesisi926T → M: No effect on kinase activity. 1 Publication1
Mutagenesisi947I → R: Constitutively autophosphorylated. 1 Publication1
Mutagenesisi992R → A: Abolishes APC/C-mediated degradation; when associated with A-995 and A-1000. 1 Publication1
Mutagenesisi995L → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-1000. 1 Publication1
Mutagenesisi1000D → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-995. 1 Publication1
Mutagenesisi1035Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1301. 1 Publication1
Mutagenesisi1056Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. Promotes nuclear translocation of ERBB4 intracellular domain E4ICD1. 1 Publication1
Mutagenesisi1056Y → F: Abolishes interaction with WWP1; when associated with F-1301. 1 Publication1
Mutagenesisi1301Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. 3 Publications1
Mutagenesisi1301Y → 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 Publications1
Mutagenesisi1301Y → F: Abolishes interaction with WWP1; when associated with F-1056. 3 Publications1

Keywords - Diseasei

Amyotrophic lateral sclerosis, Disease mutation, Neurodegeneration

Organism-specific databases

DisGeNETi2066.
MalaCardsiERBB4.
MIMi615515. phenotype.
OpenTargetsiENSG00000178568.
Orphaneti803. Amyotrophic lateral sclerosis.
PharmGKBiPA27847.

Chemistry databases

ChEMBLiCHEMBL3009.
DrugBankiDB08916. Afatinib.
GuidetoPHARMACOLOGYi1799.

Polymorphism and mutation databases

BioMutaiERBB4.
DMDMi3913590.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 25Sequence analysisAdd BLAST25
ChainiPRO_000001667426 – 1308Receptor tyrosine-protein kinase erbB-4Add BLAST1283
ChainiPRO_0000396797676 – 1308ERBB4 intracellular domainBy similarityAdd BLAST633

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi29 ↔ 561 Publication
Glycosylationi138N-linked (GlcNAc...)1 Publication1
Disulfide bondi156 ↔ 1861 Publication
Glycosylationi174N-linked (GlcNAc...)1 Publication1
Glycosylationi181N-linked (GlcNAc...)Sequence analysis1
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
Glycosylationi253N-linked (GlcNAc...)1 Publication1
Disulfide bondi262 ↔ 2891 Publication
Disulfide bondi293 ↔ 3041 Publication
Disulfide bondi308 ↔ 3231 Publication
Disulfide bondi326 ↔ 3301 Publication
Glycosylationi358N-linked (GlcNAc...)1 Publication1
Glycosylationi410N-linked (GlcNAc...)1 Publication1
Glycosylationi473N-linked (GlcNAc...)1 Publication1
Glycosylationi495N-linked (GlcNAc...)1 Publication1
Disulfide bondi503 ↔ 5121 Publication
Disulfide bondi507 ↔ 5201 Publication
Disulfide bondi523 ↔ 5321 Publication
Disulfide bondi536 ↔ 5521 Publication
Glycosylationi548N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi555 ↔ 5691 Publication
Disulfide bondi559 ↔ 5771 Publication
Glycosylationi576N-linked (GlcNAc...)1 Publication1
Disulfide bondi580 ↔ 5891 Publication
Disulfide bondi593 ↔ 6141 Publication
Disulfide bondi617 ↔ 6251 Publication
Glycosylationi620N-linked (GlcNAc...)Sequence analysis1
Disulfide bondi621 ↔ 6331 Publication
Modified residuei875Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1035Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1056Phosphotyrosine; by autocatalysis3 Publications1
Modified residuei1150Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1162Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1188Phosphotyrosine; by autocatalysis2 Publications1
Modified residuei1202Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1242Phosphotyrosine; by autocatalysis2 Publications1
Modified residuei1258Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei1284Phosphotyrosine; by autocatalysis1 Publication1

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.
PeptideAtlasiQ15303.
PRIDEiQ15303.

PTM databases

iPTMnetiQ15303.
PhosphoSitePlusiQ15303.

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

BgeeiENSG00000178568.
CleanExiHS_ERBB4.
ExpressionAtlasiQ15303. baseline and differential.
GenevisibleiQ15303. HS.

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
ERBB2P046263EBI-80371,EBI-641062
ERBB3P218604EBI-80371,EBI-720706
HSP90AB1P082382EBI-80371,EBI-352572
SHC1P293532EBI-80371,EBI-78835
YAP1P469373EBI-80371,EBI-1044059

GO - Molecular functioni

  • epidermal growth factor receptor binding Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi108378. 49 interactors.
DIPiDIP-29650N.
IntActiQ15303. 25 interactors.
MINTiMINT-125091.
STRINGi9606.ENSP00000342235.

Chemistry databases

BindingDBiQ15303.

Structurei

Secondary structure

11308
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi28 – 30Combined sources3
Beta strandi38 – 41Combined sources4
Helixi42 – 53Combined sources12
Beta strandi57 – 61Combined sources5
Beta strandi63 – 67Combined sources5
Helixi75 – 79Combined sources5
Beta strandi82 – 85Combined sources4
Beta strandi87 – 91Combined sources5
Beta strandi95 – 98Combined sources4
Turni112 – 114Combined sources3
Beta strandi115 – 120Combined sources6
Beta strandi125 – 128Combined sources4
Beta strandi133 – 135Combined sources3
Beta strandi144 – 150Combined sources7
Helixi158 – 160Combined sources3
Helixi163 – 165Combined sources3
Helixi173 – 175Combined sources3
Beta strandi176 – 178Combined sources3
Turni191 – 193Combined sources3
Beta strandi197 – 201Combined sources5
Helixi202 – 204Combined sources3
Beta strandi221 – 225Combined sources5
Helixi226 – 228Combined sources3
Beta strandi234 – 242Combined sources9
Beta strandi245 – 254Combined sources10
Beta strandi257 – 261Combined sources5
Beta strandi265 – 269Combined sources5
Turni270 – 273Combined sources4
Beta strandi274 – 277Combined sources4
Beta strandi283 – 285Combined sources3
Beta strandi288 – 292Combined sources5
Beta strandi298 – 300Combined sources3
Beta strandi303 – 307Combined sources5
Beta strandi312 – 317Combined sources6
Beta strandi320 – 325Combined sources6
Beta strandi327 – 329Combined sources3
Beta strandi333 – 335Combined sources3
Helixi340 – 342Combined sources3
Turni350 – 352Combined sources3
Helixi353 – 356Combined sources4
Beta strandi360 – 364Combined sources5
Beta strandi366 – 368Combined sources3
Helixi370 – 374Combined sources5
Helixi377 – 379Combined sources3
Helixi386 – 394Combined sources9
Beta strandi397 – 400Combined sources4
Beta strandi402 – 405Combined sources4
Helixi415 – 417Combined sources3
Beta strandi432 – 438Combined sources7
Beta strandi455 – 461Combined sources7
Helixi469 – 471Combined sources3
Helixi474 – 476Combined sources3
Beta strandi479 – 482Combined sources4
Beta strandi485 – 487Combined sources3
Beta strandi489 – 491Combined sources3
Helixi493 – 497Combined sources5
Turni498 – 500Combined sources3
Beta strandi512 – 516Combined sources5
Beta strandi519 – 528Combined sources10
Beta strandi531 – 534Combined sources4
Beta strandi537 – 543Combined sources7
Beta strandi545 – 548Combined sources4
Beta strandi551 – 554Combined sources4
Beta strandi568 – 573Combined sources6
Beta strandi576 – 585Combined sources10
Beta strandi588 – 592Combined sources5
Beta strandi595 – 608Combined sources14
Beta strandi612 – 616Combined sources5
Beta strandi625 – 629Combined sources5
Helixi651 – 676Combined sources26
Helixi715 – 717Combined sources3
Beta strandi718 – 729Combined sources12
Beta strandi731 – 737Combined sources7
Beta strandi740 – 743Combined sources4
Beta strandi746 – 752Combined sources7
Helixi762 – 773Combined sources12
Beta strandi778 – 780Combined sources3
Beta strandi783 – 787Combined sources5
Beta strandi789 – 791Combined sources3
Beta strandi793 – 797Combined sources5
Helixi804 – 810Combined sources7
Helixi812 – 814Combined sources3
Helixi817 – 836Combined sources20
Helixi846 – 848Combined sources3
Beta strandi849 – 853Combined sources5
Beta strandi856 – 859Combined sources4
Helixi864 – 869Combined sources6
Helixi884 – 886Combined sources3
Helixi889 – 893Combined sources5
Helixi899 – 914Combined sources16
Turni920 – 923Combined sources4
Turni926 – 928Combined sources3
Helixi929 – 934Combined sources6
Helixi947 – 955Combined sources9
Helixi961 – 963Combined sources3
Helixi967 – 977Combined sources11
Helixi981 – 983Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ15303.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini718 – 985Protein kinasePROSITE-ProRule annotationAdd BLAST268

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi676 – 684Nuclear localization signal9
Motifi1032 – 1035PPxY motif 14
Motifi1053 – 1056PPxY motif 24
Motifi1298 – 1301PPxY motif 34
Motifi1306 – 1308PDZ-binding3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi186 – 334Cys-richAdd BLAST149
Compositional biasi496 – 633Cys-richAdd BLAST138

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

eggNOGiKOG1025. Eukaryota.
ENOG410XNSR. LUCA.
GeneTreeiENSGT00760000118799.
HOGENOMiHOG000230982.
HOVERGENiHBG000490.
InParanoidiQ15303.
KOiK05085.
OMAiRTRIDSN.
OrthoDBiEOG091G00EY.
PhylomeDBiQ15303.
TreeFamiTF106002.

Family and domain databases

Gene3Di3.80.20.20. 2 hits.
InterProiIPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR032778. GF_recep_IV.
IPR009030. Growth_fac_rcpt_.
IPR011009. Kinase-like_dom.
IPR032675. L_dom-like.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR000494. Rcpt_L-dom.
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.
PF14843. GF_recep_IV. 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]
SUPFAMiSSF52058. SSF52058. 2 hits.
SSF56112. 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. AlignAdd to basket

Isoform JM-A CYT-1 (identifier: Q15303-1) [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)DescriptionActionsGraphical viewLength
Natural variantiVAR_042113140T → I in a colorectal adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_042114303S → Y in a lung squamous cell carcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_070810927R → Q in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 PublicationCorresponds to variant rs397514262dbSNPEnsembl.1
Natural variantiVAR_0708111275R → W in ALS19; reduces autophosphorylation upon NRG1 stimulation. 1 PublicationCorresponds to variant rs397514263dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_002895626 – 648NGPTS…LPQHA → IGSSIEDCIGLMD in isoform JM-B CYT-1 and isoform JM-B CYT-2. 2 PublicationsAdd BLAST23
Alternative sequenceiVSP_0221481046 – 1061Missing in isoform JM-A CYT-2 and isoform JM-B CYT-2. 2 PublicationsAdd BLAST16

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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_005246376.2. [Q15303-2]
XP_005246434.1. XM_005246377.2. [Q15303-4]
UniGeneiHs.390729.

Genome annotation databases

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

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
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_005246376.2. [Q15303-2]
XP_005246434.1. XM_005246377.2. [Q15303-4]
UniGeneiHs.390729.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB 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.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi108378. 49 interactors.
DIPiDIP-29650N.
IntActiQ15303. 25 interactors.
MINTiMINT-125091.
STRINGi9606.ENSP00000342235.

Chemistry databases

BindingDBiQ15303.
ChEMBLiCHEMBL3009.
DrugBankiDB08916. Afatinib.
GuidetoPHARMACOLOGYi1799.

Protein family/group databases

TCDBi1.A.87.2.6. the mechanosensitive calcium channel (mca) family.

PTM databases

iPTMnetiQ15303.
PhosphoSitePlusiQ15303.

Polymorphism and mutation databases

BioMutaiERBB4.
DMDMi3913590.

Proteomic databases

MaxQBiQ15303.
PaxDbiQ15303.
PeptideAtlasiQ15303.
PRIDEiQ15303.

Protocols and materials databases

DNASUi2066.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

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

Organism-specific databases

CTDi2066.
DisGeNETi2066.
GeneCardsiERBB4.
HGNCiHGNC:3432. ERBB4.
HPAiCAB000276.
CAB025522.
HPA012016.
MalaCardsiERBB4.
MIMi600543. gene.
615515. phenotype.
neXtProtiNX_Q15303.
OpenTargetsiENSG00000178568.
Orphaneti803. Amyotrophic lateral sclerosis.
PharmGKBiPA27847.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG1025. Eukaryota.
ENOG410XNSR. LUCA.
GeneTreeiENSGT00760000118799.
HOGENOMiHOG000230982.
HOVERGENiHBG000490.
InParanoidiQ15303.
KOiK05085.
OMAiRTRIDSN.
OrthoDBiEOG091G00EY.
PhylomeDBiQ15303.
TreeFamiTF106002.

Enzyme and pathway databases

BioCyciZFISH:HS17081-MONOMER.
BRENDAi2.7.10.1. 2681.
ReactomeiR-HSA-1227986. Signaling by ERBB2.
R-HSA-1236394. Signaling by ERBB4.
R-HSA-1250196. SHC1 events in ERBB2 signaling.
R-HSA-1250342. PI3K events in ERBB4 signaling.
R-HSA-1250347. SHC1 events in ERBB4 signaling.
R-HSA-1251985. Nuclear signaling by ERBB4.
R-HSA-1253288. Downregulation of ERBB4 signaling.
R-HSA-1257604. PIP3 activates AKT signaling.
R-HSA-1963640. GRB2 events in ERBB2 signaling.
R-HSA-1963642. PI3K events in ERBB2 signaling.
R-HSA-2219530. Constitutive Signaling by Aberrant PI3K in Cancer.
R-HSA-5673001. RAF/MAP kinase cascade.
R-HSA-6785631. ERBB2 Regulates Cell Motility.
R-HSA-6811558. PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
R-HSA-8847993. ERBB2 Activates PTK6 Signaling.
R-HSA-8863795. Downregulation of ERBB2 signaling.
SignaLinkiQ15303.
SIGNORiQ15303.

Miscellaneous databases

ChiTaRSiERBB4. human.
EvolutionaryTraceiQ15303.
GeneWikiiERBB4.
GenomeRNAii2066.
PMAP-CutDBQ15303.
PROiQ15303.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000178568.
CleanExiHS_ERBB4.
ExpressionAtlasiQ15303. baseline and differential.
GenevisibleiQ15303. HS.

Family and domain databases

Gene3Di3.80.20.20. 2 hits.
InterProiIPR006211. Furin-like_Cys-rich_dom.
IPR006212. Furin_repeat.
IPR032778. GF_recep_IV.
IPR009030. Growth_fac_rcpt_.
IPR011009. Kinase-like_dom.
IPR032675. L_dom-like.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR000494. Rcpt_L-dom.
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.
PF14843. GF_recep_IV. 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]
SUPFAMiSSF52058. SSF52058. 2 hits.
SSF56112. 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]
ProtoNetiSearch...

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: November 30, 2016
This is version 191 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

Caution

Conflicting reports about the role of ERBB4 in mediating apoptosis, differentiation, or tumor cell proliferation may be explained by the opposite functions of the different isoforms and their intracellular fragments, and by the formation of heterodimers with other EGF receptor family members (PubMed:18454307 and PubMed:21811097). Thus, heterodimer formation of a kinase-dead ERBB4 mutant with ERBB2 is sufficient for the activation of AKT1, MAPK1/ERK2 and MAPK3/ERK1 (PubMed:19098003).1 Publication

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

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.