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Q15303 (ERBB4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 166. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended 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:

  1. ERBB4 intracellular domain
    Short name=4ICD
    Short name=E4ICD
    Alternative name(s):
    s80HER4
Gene names
Name:ERBB4
Synonyms:HER4
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1308 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-ACYT-1 and isoform JM-BCYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-ACYT-1 and isoform JM-BCYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-ACYT-2 and isoform JM-BCYT-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-ACYT-1 and isoform JM-ACYT-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. Ref.1 Ref.2 Ref.7 Ref.9 Ref.10 Ref.14 Ref.15 Ref.16 Ref.17 Ref.19 Ref.21 Ref.22 Ref.23 Ref.25 Ref.27 Ref.28 Ref.30 Ref.31 Ref.33 Ref.35 Ref.38 Ref.40

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.7 Ref.38 Ref.50 Ref.51

Enzyme regulation

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. Ref.7 Ref.21 Ref.38 Ref.41 Ref.51

Subunit structure

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-ACYT-2) with YAP1 (via the WW domain 1 of isoform 1) Interacts (isoform JM-ACYT-1 and isoform JM-BCYT-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-ACYT-1 and isoform JM-BCYT-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. Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13 Ref.14 Ref.15 Ref.16 Ref.19 Ref.20 Ref.23 Ref.24 Ref.25 Ref.26 Ref.28 Ref.29 Ref.31 Ref.34 Ref.36 Ref.37 Ref.38 Ref.39 Ref.40 Ref.51

Subcellular location

Cell membrane; Single-pass type I membrane protein. Note: In response to NRG1 treatment, the activated receptor is internalized. Ref.1 Ref.2 Ref.16 Ref.23 Ref.25 Ref.28 Ref.30 Ref.31 Ref.33 Ref.35 Ref.37 Ref.40

ERBB4 intracellular domain: Nucleus. Mitochondrion. 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. Ref.1 Ref.2 Ref.16 Ref.23 Ref.25 Ref.28 Ref.30 Ref.31 Ref.33 Ref.35 Ref.37 Ref.40

Tissue specificity

Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-ACYT-1 and isoform JM-BCYT-1 are expressed in cerebellum, but only the isoform JM-Bis expressed in the heart. Ref.1 Ref.2 Ref.15

Post-translational modification

Isoform JM-ACYT-1 and isoform JM-ACYT-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-ACYT-1 are more readily degraded by the proteasome than fragments of isoform JM-ACYT-2, suggesting a prevalence of E4ICD2 over E4ICD1. Isoform JM-BCYT-1 and isoform JM-BCYT-2 lack the ADAM17 cleavage site and are not processed by ADAM17, precluding further processing by gamma-secretase.

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-ACYT-2 is constitutively phosphorylated on tyrosine residues in a ligand-independent manner. E4ICD2 but not E4ICD1 is phosphorylated on tyrosine residues. Ref.1 Ref.2 Ref.5 Ref.6 Ref.7 Ref.8 Ref.9 Ref.10 Ref.11 Ref.12 Ref.15 Ref.17 Ref.19 Ref.21 Ref.30 Ref.31 Ref.32 Ref.34 Ref.35 Ref.36 Ref.38 Ref.50 Ref.51

Ubiquitinated. During mitosis, the ERBB4 intracellular domain is ubiquitinated by the APC/C complex and targeted to proteasomal degradation. Isoform JM-ACYT-1 and isoform JM-BCYT-1 are ubiquitinated by WWP1. The ERBB4 intracellular domain (E4ICD1) is ubiquitinated, and this involves NEDD4. Ref.33 Ref.37

Involvement in disease

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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.53

Sequence similarities

Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily.

Contains 1 protein kinase domain.

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 (Ref.46 and Ref.48). Thus, heterodimer formation of a kinase-dead ERBB4 mutant with ERBB2 is sufficient for the activation of AKT1, MAPK1/ERK2 and MAPK3/ERK1 (Ref.38).

Ontologies

Keywords
   Biological processApoptosis
Lactation
Transcription
Transcription regulation
   Cellular componentCell membrane
Membrane
Mitochondrion
Nucleus
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseAmyotrophic lateral sclerosis
Disease mutation
Neurodegeneration
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionActivator
Developmental protein
Kinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processFc-epsilon receptor signaling pathway

Traceable author statement. Source: Reactome

cardiac muscle tissue regeneration

Inferred from sequence or structural similarity. Source: UniProtKB

cell fate commitment

Inferred from electronic annotation. Source: Ensembl

cell migration

Inferred from direct assay Ref.9. Source: UniProtKB

cell proliferation

Traceable author statement Ref.1. Source: ProtInc

central nervous system morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

embryonic pattern specification

Inferred from sequence or structural similarity. Source: UniProtKB

epidermal growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

fibroblast growth factor receptor signaling pathway

Traceable author statement. Source: Reactome

heart development

Inferred from sequence or structural similarity. Source: UniProtKB

innate immune response

Traceable author statement. Source: Reactome

lactation

Inferred from mutant phenotype Ref.25. Source: UniProtKB

mammary gland alveolus development

Inferred from sequence or structural similarity. Source: UniProtKB

mammary gland epithelial cell differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

mitochondrial fragmentation involved in apoptotic process

Inferred from mutant phenotype Ref.28. Source: UniProtKB

negative regulation of apoptotic process

Inferred from mutant phenotype Ref.17. Source: UniProtKB

negative regulation of cell proliferation

Inferred from mutant phenotype Ref.32. Source: UniProtKB

nervous system development

Inferred from sequence or structural similarity. Source: UniProtKB

neural crest cell migration

Inferred from sequence or structural similarity. Source: UniProtKB

neurotrophin TRK receptor signaling pathway

Traceable author statement. Source: Reactome

olfactory bulb interneuron differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-tyrosine phosphorylation

Inferred from direct assay Ref.51. Source: UniProtKB

phosphatidylinositol-mediated signaling

Traceable author statement. Source: Reactome

positive regulation of ERK1 and ERK2 cascade

Inferred from mutant phenotype Ref.16. Source: UniProtKB

positive regulation of STAT protein import into nucleus

Inferred from mutant phenotype Ref.25. Source: UniProtKB

positive regulation of cardiac muscle cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

positive regulation of cell proliferation

Inferred from mutant phenotype Ref.7Ref.9. Source: UniProtKB

positive regulation of phosphatidylinositol 3-kinase activity

Inferred from direct assay Ref.15. Source: UniProtKB

positive regulation of protein phosphorylation

Traceable author statement Ref.25. Source: UniProtKB

positive regulation of transcription, DNA-templated

Inferred from mutant phenotype Ref.25. Source: UniProtKB

positive regulation of tyrosine phosphorylation of Stat5 protein

Inferred from mutant phenotype Ref.31. Source: UniProtKB

protein autophosphorylation

Inferred from direct assay Ref.51. Source: UniProtKB

regulation of cell migration

Inferred from sequence or structural similarity. Source: UniProtKB

signal transduction

Inferred from direct assay PubMed 10572067. Source: UniProtKB

transcription, DNA-templated

Inferred from electronic annotation. Source: UniProtKB-KW

transmembrane receptor protein tyrosine kinase signaling pathway

Inferred from direct assay Ref.15Ref.51. Source: UniProtKB

   Cellular_componentbasolateral plasma membrane

Inferred from direct assay PubMed 12646923. Source: BHF-UCL

cytosol

Traceable author statement. Source: Reactome

extracellular region

Traceable author statement. Source: Reactome

integral component of membrane

Inferred from electronic annotation. Source: UniProtKB-KW

mitochondrial matrix

Traceable author statement. Source: Reactome

mitochondrion

Inferred from direct assay Ref.28. Source: UniProtKB

nucleoplasm

Traceable author statement. Source: Reactome

nucleus

Inferred from direct assay Ref.25. Source: UniProtKB

plasma membrane

Traceable author statement. Source: Reactome

receptor complex

Inferred from direct assay PubMed 23382219. Source: MGI

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

epidermal growth factor receptor binding

Inferred from physical interaction Ref.7. Source: UniProtKB

protein binding

Inferred from physical interaction PubMed 10572067PubMed 11867753Ref.39Ref.40Ref.11. Source: UniProtKB

protein homodimerization activity

Inferred from physical interaction Ref.51. Source: UniProtKB

protein tyrosine kinase activity

Inferred from direct assay Ref.51. Source: UniProtKB

receptor signaling protein tyrosine kinase activity

Inferred from electronic annotation. Source: InterPro

transcription regulatory region DNA binding

Inferred from mutant phenotype Ref.25. Source: UniProtKB

transmembrane receptor protein tyrosine kinase activity

Inferred from direct assay Ref.51. Source: UniProtKB

Complete GO annotation...

Alternative products

This entry describes 4 isoforms produced by alternative splicing. [Align] [Select]
Isoform JM-A CYT-1 (identifier: Q15303-1)

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.
Note: Proteolytical processing generates E4ICD1 (s80Cyt1).
Isoform JM-B CYT-1 (identifier: Q15303-2)

The sequence of this isoform differs from the canonical sequence as follows:
     626-648: NGPTSHDCIYYPWTGHSTLPQHA → IGSSIEDCIGLMD
Isoform JM-A CYT-2 (identifier: Q15303-3)

The sequence of this isoform differs from the canonical sequence as follows:
     1046-1061: Missing.
Note: Proteolytical processing generates E4ICD2 (s80Cyt2).
Isoform JM-B CYT-2 (identifier: Q15303-4)

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

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2525 Potential
Chain26 – 13081283Receptor tyrosine-protein kinase erbB-4
PRO_0000016674
Chain676 – 1308633ERBB4 intracellular domain By similarity
PRO_0000396797

Regions

Topological domain26 – 651626Extracellular Potential
Transmembrane652 – 67524Helical; Potential
Topological domain676 – 1308633Cytoplasmic Potential
Domain718 – 985268Protein kinase
Nucleotide binding724 – 7329ATP By similarity
Nucleotide binding797 – 7993ATP By similarity
Nucleotide binding843 – 8486ATP By similarity
Motif676 – 6849Nuclear localization signal
Motif1032 – 10354PPxY motif 1
Motif1053 – 10564PPxY motif 2
Motif1298 – 13014PPxY motif 3
Motif1306 – 13083PDZ-binding
Compositional bias186 – 334149Cys-rich
Compositional bias496 – 633138Cys-rich

Sites

Active site8431Proton acceptor By similarity
Binding site7511ATP By similarity

Amino acid modifications

Modified residue8751Phosphotyrosine; by autocatalysis Ref.36
Modified residue10351Phosphotyrosine; by autocatalysis Ref.36
Modified residue10561Phosphotyrosine; by autocatalysis Ref.7 Ref.32 Ref.36
Modified residue11501Phosphotyrosine; by autocatalysis Ref.36
Modified residue11621Phosphotyrosine; by autocatalysis Ref.36
Modified residue11881Phosphotyrosine; by autocatalysis Ref.7 Ref.36
Modified residue12021Phosphotyrosine; by autocatalysis Ref.36
Modified residue12421Phosphotyrosine; by autocatalysis Ref.7 Ref.36
Modified residue12581Phosphotyrosine; by autocatalysis Ref.36
Modified residue12841Phosphotyrosine; by autocatalysis Ref.36
Glycosylation1381N-linked (GlcNAc...) Ref.49
Glycosylation1741N-linked (GlcNAc...) Ref.49
Glycosylation1811N-linked (GlcNAc...) Potential
Glycosylation2531N-linked (GlcNAc...) Ref.49
Glycosylation3581N-linked (GlcNAc...) Ref.49
Glycosylation4101N-linked (GlcNAc...) Ref.49
Glycosylation4731N-linked (GlcNAc...) Ref.49
Glycosylation4951N-linked (GlcNAc...) Ref.49
Glycosylation5481N-linked (GlcNAc...) Potential
Glycosylation5761N-linked (GlcNAc...) Ref.49
Glycosylation6201N-linked (GlcNAc...) Potential
Disulfide bond29 ↔ 56 Ref.49
Disulfide bond156 ↔ 186 Ref.49
Disulfide bond189 ↔ 197 Ref.49
Disulfide bond193 ↔ 205 Ref.49
Disulfide bond213 ↔ 221 Ref.49
Disulfide bond217 ↔ 229 Ref.49
Disulfide bond230 ↔ 238 Ref.49
Disulfide bond234 ↔ 246 Ref.49
Disulfide bond249 ↔ 258 Ref.49
Disulfide bond262 ↔ 289 Ref.49
Disulfide bond293 ↔ 304 Ref.49
Disulfide bond308 ↔ 323 Ref.49
Disulfide bond326 ↔ 330 Ref.49
Disulfide bond503 ↔ 512 Ref.49
Disulfide bond507 ↔ 520 Ref.49
Disulfide bond523 ↔ 532 Ref.49
Disulfide bond536 ↔ 552 Ref.49
Disulfide bond555 ↔ 569 Ref.49
Disulfide bond559 ↔ 577 Ref.49
Disulfide bond580 ↔ 589 Ref.49
Disulfide bond593 ↔ 614 Ref.49
Disulfide bond617 ↔ 625 Ref.49
Disulfide bond621 ↔ 633 Ref.49

Natural variations

Alternative sequence626 – 64823NGPTS…LPQHA → IGSSIEDCIGLMD in isoform JM-B CYT-1 and isoform JM-B CYT-2.
VSP_002895
Alternative sequence1046 – 106116Missing in isoform JM-A CYT-2 and isoform JM-B CYT-2.
VSP_022148
Natural variant1401T → I in a colorectal adenocarcinoma sample; somatic mutation. Ref.52
VAR_042113
Natural variant3031S → Y in a lung squamous cell carcinoma sample; somatic mutation. Ref.52
VAR_042114
Natural variant9271R → Q in ALS19; reduces autophosphorylation upon NRG1 stimulation. Ref.53
VAR_070810
Natural variant12751R → W in ALS19; reduces autophosphorylation upon NRG1 stimulation. Ref.53
VAR_070811

Experimental info

Mutagenesis6461Q → C: Constitutively activated kinase. Ref.32
Mutagenesis6751V → A: Abolishes proteolytic processing and nuclear localization. Ref.27 Ref.33
Mutagenesis681 – 6844KKKR → EIMG: Abolishes nuclear localization of the ERBB4 intracellular domain. Ref.25
Mutagenesis7101L → N: Strongly reduced autophosphorylation. Ref.50
Mutagenesis7211V → I: No effect on kinase activity. Ref.38
Mutagenesis7511K → R: Abolishes kinase activity. Abolishes phosphorylation, proteolytic processing and nuclear localization. Ref.22 Ref.33 Ref.35
Mutagenesis7661M → R: Strongly reduced autophosphorylation. Ref.50
Mutagenesis7731A → S: No effect on kinase activity. Ref.38
Mutagenesis7821R → Q: No effect on kinase activity. Ref.38
Mutagenesis8101E → K: No effect on kinase activity. Ref.38
Mutagenesis8431D → N: Loss of kinase activity. Ref.34
Mutagenesis8541P → Q: No effect on kinase activity. Ref.38
Mutagenesis8611D → Y: Loss of kinase activity. Ref.38
Mutagenesis8641L → R: Strongly reduced autophosphorylation. Ref.50
Mutagenesis8721E → K: No effect on kinase activity. Ref.38
Mutagenesis9261T → M: No effect on kinase activity. Ref.38
Mutagenesis9471I → R: Constitutively autophosphorylated. Ref.50
Mutagenesis9921R → A: Abolishes APC/C-mediated degradation; when associated with A-995 and A-1000. Ref.33
Mutagenesis9951L → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-1000. Ref.33
Mutagenesis10001D → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-995. Ref.33
Mutagenesis10351Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1301. Ref.26
Mutagenesis10561Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. Promotes nuclear translocation of ERBB4 intracellular domain E4ICD1. Ref.39
Mutagenesis10561Y → F: Abolishes interaction with WWP1; when associated with F-1301. Ref.39
Mutagenesis13011Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. Ref.23 Ref.26 Ref.39
Mutagenesis13011Y → 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. Ref.23 Ref.26 Ref.39
Mutagenesis13011Y → F: Abolishes interaction with WWP1; when associated with F-1056. Ref.23 Ref.26 Ref.39

Secondary structure

....................................................................................................................................................................................... 1308
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform JM-A CYT-1 [UniParc].

Last modified November 1, 1996. Version 1.
Checksum: 5E4AE80985D88761

FASTA1,308146,808
        10         20         30         40         50         60 
MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM 

        70         80         90        100        110        120 
GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF 

       130        140        150        160        170        180 
LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNLTLVST 

       190        200        210        220        230        240 
NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG 

       250        260        270        280        290        300 
PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD 

       310        320        330        340        350        360 
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT 

       370        380        390        400        410        420 
KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL 

       430        440        450        460        470        480 
VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 

       490        500        510        520        530        540 
INQRIVIRDN RKAENCTAEG MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD 

       550        560        570        580        590        600 
GEFREFENGS ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 

       610        620        630        640        650        660 
NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG 

       670        680        690        700        710        720 
LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR 

       730        740        750        760        770        780 
VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL 

       790        800        810        820        830        840 
VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV 

       850        860        870        880        890        900 
HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ 

       910        920        930        940        950        960 
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID 

       970        980        990       1000       1010       1020 
ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE 

      1030       1040       1050       1060       1070       1080 
EYLVPQAFNI PPPIYTSRAR IDSNRSEIGH SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP 

      1090       1100       1110       1120       1130       1140 
YRAPTSTIPE APVAQGATAE IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS 

      1150       1160       1170       1180       1190       1200 
PRGELDEEGY MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED 

      1210       1220       1230       1240       1250       1260 
EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ 

      1270       1280       1290       1300 
EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP YRHRNTVV 

« Hide

Isoform JM-B CYT-1 [UniParc].

Checksum: 346C1288AD041961
Show »

FASTA1,298145,578
Isoform JM-A CYT-2 [UniParc].

Checksum: 60C0DFD446C7FA89
Show »

FASTA1,292145,198
Isoform JM-B CYT-2 [UniParc].

Checksum: 68F27777BC9E2F74
Show »

FASTA1,282143,968

References

« Hide 'large scale' references
[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]"Role of ErbB4 in breast cancer."
Sundvall M., Iljin K., Kilpinen S., Sara H., Kallioniemi O.P., Elenius K.
J. Mammary Gland Biol. Neoplasia 13:259-268(2008) [PubMed] [Europe PMC] [Abstract]
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]"6-Ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-anilines as tunable covalent modifiers of ErbB kinases."
Wood E.R., Shewchuk L.M., Ellis B., Brignola P., Brashear R.L., Caferro T.R., Dickerson S.H., Dickson H.D., Donaldson K.H., Gaul M., Griffin R.J., Hassell A.M., Keith B., Mullin R., Petrov K.G., Reno M.J., Rusnak D.W., Tadepalli S.M. expand/collapse author list , Ulrich J.C., Wagner C.D., Vanderwall D.E., Waterson A.G., Williams J.D., White W.L., Uehling D.E.
Proc. Natl. Acad. Sci. U.S.A. 105:2773-2778(2008) [PubMed] [Europe PMC] [Abstract]
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]"Mechanism of activation and inhibition of the HER4/ErbB4 kinase."
Qiu C., Tarrant M.K., Choi S.H., Sathyamurthy A., Bose R., Banjade S., Pal A., Bornmann W.G., Lemmon M.A., Cole P.A., Leahy D.J.
Structure 16:460-467(2008) [PubMed] [Europe PMC] [Abstract]
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. expand/collapse author list , 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. expand/collapse author list , 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.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
CCDSCCDS2394.1. [Q15303-1]
CCDS42811.1. [Q15303-3]
PIRA47253.
RefSeqNP_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]
UniGeneHs.390729.

3D structure databases

PDBe
RCSB-PDB
PDBj
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[»]
ProteinModelPortalQ15303.
SMRQ15303. Positions 26-639, 642-1074.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108378. 45 interactions.
DIPDIP-29650N.
IntActQ15303. 19 interactions.
MINTMINT-125091.
STRING9606.ENSP00000342235.

Chemistry

BindingDBQ15303.
ChEMBLCHEMBL3009.
GuidetoPHARMACOLOGY1799.

PTM databases

PhosphoSiteQ15303.

Polymorphism databases

DMDM3913590.

Proteomic databases

MaxQBQ15303.
PaxDbQ15303.
PRIDEQ15303.

Protocols and materials databases

DNASU2066.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000342788; ENSP00000342235; ENSG00000178568. [Q15303-1]
ENST00000402597; ENSP00000385565; ENSG00000178568. [Q15303-2]
ENST00000436443; ENSP00000403204; ENSG00000178568. [Q15303-3]
GeneID2066.
KEGGhsa:2066.
UCSCuc002veg.1. human. [Q15303-1]
uc002veh.1. human. [Q15303-3]
uc010zji.1. human. [Q15303-2]
uc010zjj.1. human. [Q15303-4]

Organism-specific databases

CTD2066.
GeneCardsGC02M212210.
HGNCHGNC:3432. ERBB4.
HPACAB000276.
CAB025522.
HPA012016.
MIM600543. gene.
615515. phenotype.
neXtProtNX_Q15303.
Orphanet803. Amyotrophic lateral sclerosis.
PharmGKBPA27847.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000230982.
HOVERGENHBG000490.
InParanoidQ15303.
KOK05085.
OMARTRIDSN.
OrthoDBEOG7V49XM.
PhylomeDBQ15303.
TreeFamTF106002.

Enzyme and pathway databases

BRENDA2.7.10.1. 2681.
ReactomeREACT_111102. Signal Transduction.
REACT_116125. Disease.
REACT_6900. Immune System.
SignaLinkQ15303.

Gene expression databases

ArrayExpressQ15303.
BgeeQ15303.
CleanExHS_ERBB4.
GenevestigatorQ15303.

Family and domain databases

Gene3D3.80.20.20. 2 hits.
InterProIPR000494. 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]
PfamPF00757. Furin-like. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
[Graphical view]
PIRSFPIRSF000619. TyrPK_EGF-R. 1 hit.
PRINTSPR00109. TYRKINASE.
SMARTSM00261. FU. 5 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 2 hits.
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

ChiTaRSERBB4. human.
EvolutionaryTraceQ15303.
GeneWikiERBB4.
GenomeRNAi2066.
NextBio8397.
PMAP-CutDBQ15303.
PROQ15303.
SOURCESearch...

Entry information

Entry nameERBB4_HUMAN
AccessionPrimary (citable) accession number: Q15303
Secondary accession number(s): B7ZLD7 expand/collapse secondary AC list , B7ZLE2, B7ZLE3, Q2M1W1, Q59EW4
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: November 1, 1996
Last modified: July 9, 2014
This is version 166 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 2

Human chromosome 2: entries, gene names and cross-references to MIM