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Q15303

- ERBB4_HUMAN

UniProt

Q15303 - ERBB4_HUMAN

Protein

Receptor tyrosine-protein kinase erbB-4

Gene

ERBB4

Organism
Homo sapiens (Human)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 168 (01 Oct 2014)
      Sequence version 1 (01 Nov 1996)
      Previous versions | rss
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    Functioni

    Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell proliferation, differentiation, migration and apoptosis. Required for normal cardiac muscle differentiation during embryonic development, and for postnatal cardiomyocyte proliferation. Required for normal development of the embryonic central nervous system, especially for normal neural crest cell migration and normal axon guidance. Required for mammary gland differentiation, induction of milk proteins and lactation. Acts as cell-surface receptor for the neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Ligand specificity and signaling is modulated by alternative splicing, proteolytic processing, and by the formation of heterodimers with other ERBB family members, thereby creating multiple combinations of intracellular phosphotyrosines that trigger ligand- and context-specific cellular responses. Mediates phosphorylation of SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Isoform JM-A CYT-1 and isoform JM-B CYT-1 phosphorylate PIK3R1, leading to the activation of phosphatidylinositol 3-kinase and AKT1 and protect cells against apoptosis. Isoform JM-A CYT-1 and isoform JM-B CYT-1 mediate reorganization of the actin cytoskeleton and promote cell migration in response to NRG1. Isoform JM-A CYT-2 and isoform JM-B CYT-2 lack the phosphotyrosine that mediates interaction with PIK3R1, and hence do not phosphorylate PIK3R1, do not protect cells against apoptosis, and do not promote reorganization of the actin cytoskeleton and cell migration. Proteolytic processing of isoform JM-A CYT-1 and isoform JM-A CYT-2 gives rise to the corresponding soluble intracellular domains (4ICD) that translocate to the nucleus, promote nuclear import of STAT5A, activation of STAT5A, mammary epithelium differentiation, cell proliferation and activation of gene expression. The ERBB4 soluble intracellular domains (4ICD) colocalize with STAT5A at the CSN2 promoter to regulate transcription of milk proteins during lactation. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.22 Publications

    Catalytic activityi

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

    Enzyme regulationi

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

    Sites

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

    Regions

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

    GO - Molecular functioni

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

    GO - Biological processi

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

    Keywords - Molecular functioni

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

    Keywords - Biological processi

    Apoptosis, Lactation, Transcription, Transcription regulation

    Keywords - Ligandi

    ATP-binding, Nucleotide-binding

    Enzyme and pathway databases

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

    Names & Taxonomyi

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

    Organism-specific databases

    HGNCiHGNC:3432. ERBB4.

    Subcellular locationi

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

    GO - Cellular componenti

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

    Keywords - Cellular componenti

    Cell membrane, Membrane, Mitochondrion, Nucleus

    Pathology & Biotechi

    Involvement in diseasei

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

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi646 – 6461Q → C: Constitutively activated kinase. 2 Publications
    Mutagenesisi675 – 6751V → A: Abolishes proteolytic processing and nuclear localization. 3 Publications
    Mutagenesisi681 – 6844KKKR → EIMG: Abolishes nuclear localization of the ERBB4 intracellular domain. 1 Publication
    Mutagenesisi710 – 7101L → N: Strongly reduced autophosphorylation. 2 Publications
    Mutagenesisi721 – 7211V → I: No effect on kinase activity. 2 Publications
    Mutagenesisi751 – 7511K → R: Abolishes kinase activity. Abolishes phosphorylation, proteolytic processing and nuclear localization. 4 Publications
    Mutagenesisi766 – 7661M → R: Strongly reduced autophosphorylation. 2 Publications
    Mutagenesisi773 – 7731A → S: No effect on kinase activity. 2 Publications
    Mutagenesisi782 – 7821R → Q: No effect on kinase activity. 2 Publications
    Mutagenesisi810 – 8101E → K: No effect on kinase activity. 2 Publications
    Mutagenesisi843 – 8431D → N: Loss of kinase activity. 2 Publications
    Mutagenesisi854 – 8541P → Q: No effect on kinase activity. 2 Publications
    Mutagenesisi861 – 8611D → Y: Loss of kinase activity. 2 Publications
    Mutagenesisi864 – 8641L → R: Strongly reduced autophosphorylation. 2 Publications
    Mutagenesisi872 – 8721E → K: No effect on kinase activity. 2 Publications
    Mutagenesisi926 – 9261T → M: No effect on kinase activity. 2 Publications
    Mutagenesisi947 – 9471I → R: Constitutively autophosphorylated. 2 Publications
    Mutagenesisi992 – 9921R → A: Abolishes APC/C-mediated degradation; when associated with A-995 and A-1000. 2 Publications
    Mutagenesisi995 – 9951L → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-1000. 2 Publications
    Mutagenesisi1000 – 10001D → A: Abolishes APC/C-mediated degradation; when associated with A-992 and A-995. 2 Publications
    Mutagenesisi1035 – 10351Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1301. 2 Publications
    Mutagenesisi1056 – 10561Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. Promotes nuclear translocation of ERBB4 intracellular domain E4ICD1. 2 Publications
    Mutagenesisi1056 – 10561Y → F: Abolishes interaction with WWP1; when associated with F-1301. 2 Publications
    Mutagenesisi1301 – 13011Y → A: Abolishes interaction with NEDD4 and impairs ubiquitination. 4 Publications
    Mutagenesisi1301 – 13011Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1035. Loss of interaction with YAP1 and stimulation of transcription. 4 Publications
    Mutagenesisi1301 – 13011Y → F: Abolishes interaction with WWP1; when associated with F-1056. 4 Publications

    Keywords - Diseasei

    Amyotrophic lateral sclerosis, Disease mutation, Neurodegeneration

    Organism-specific databases

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

    PTM / Processingi

    Molecule processing

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

    Amino acid modifications

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

    Post-translational modificationi

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

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

    Proteomic databases

    MaxQBiQ15303.
    PaxDbiQ15303.
    PRIDEiQ15303.

    PTM databases

    PhosphoSiteiQ15303.

    Miscellaneous databases

    PMAP-CutDBQ15303.

    Expressioni

    Tissue specificityi

    Expressed at highest levels in brain, heart, kidney, in addition to skeletal muscle, parathyroid, cerebellum, pituitary, spleen, testis and breast. Lower levels in thymus, lung, salivary gland, and pancreas. Isoform JM-A CYT-1 and isoform JM-B CYT-1 are expressed in cerebellum, but only the isoform JM-B is expressed in the heart.3 Publications

    Gene expression databases

    ArrayExpressiQ15303.
    BgeeiQ15303.
    CleanExiHS_ERBB4.
    GenevestigatoriQ15303.

    Organism-specific databases

    HPAiCAB000276.
    CAB025522.
    HPA012016.

    Interactioni

    Subunit structurei

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

    Binary interactionsi

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

    Protein-protein interaction databases

    BioGridi108378. 45 interactions.
    DIPiDIP-29650N.
    IntActiQ15303. 20 interactions.
    MINTiMINT-125091.
    STRINGi9606.ENSP00000342235.

    Structurei

    Secondary structure

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

    3D structure databases

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

    Miscellaneous databases

    EvolutionaryTraceiQ15303.

    Topological domain

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

    Transmembrane

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

    Family & Domainsi

    Domains and Repeats

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

    Motif

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

    Compositional bias

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

    Sequence similaritiesi

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

    Keywords - Domaini

    Repeat, Signal, Transmembrane, Transmembrane helix

    Phylogenomic databases

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

    Family and domain databases

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

    Sequences (4)i

    Sequence statusi: Complete.

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

    This entry describes 4 isoformsi produced by alternative splicing. Align

    Isoform JM-A CYT-1 (identifier: Q15303-1) [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

    MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR     50
    KYYENCEVVM GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE 100
    NLRIIRGTKL YEDRYALAIF LNYRKDGNFG LQELGLKNLT EILNGGVYVD 150
    QNKFLCYADT IHWQDIVRNP WPSNLTLVST NGSSGCGRCH KSCTGRCWGP 200
    TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG PKDTDCFACM 250
    NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD 300
    SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS 350
    SNIDKFINCT KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG 400
    FLNIQSWPPN MTDFSVFSNL VTIGGRVLYS GLSLLILKQQ GITSLQFQSL 450
    KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RKAENCTAEG 500
    MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD GEFREFENGS 550
    ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 600
    NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART 650
    PLIAAGVIGG LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP 700
    SGTAPNQAQL RILKETELKR VKVLGSGAFG TVYKGIWVPE GETVKIPVAI 750
    KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP TIQLVTQLMP 800
    HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV HRDLAARNVL 850
    VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ 900
    SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY 950
    MVMVKCWMID ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND 1000
    SKFFQNLLDE EDLEDMMDAE EYLVPQAFNI PPPIYTSRAR IDSNRSEIGH 1050
    SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP YRAPTSTIPE APVAQGATAE 1100
    IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS PRGELDEEGY 1150
    MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED 1200
    EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR 1250
    STLQHPDYLQ EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP 1300
    YRHRNTVV 1308

    Note: Proteolytical processing generates E4ICD1 (s80Cyt1).

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

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

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

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

    Note: Proteolytical processing generates E4ICD2 (s80Cyt2).

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

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

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

    Natural variant

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

    Alternative sequence

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

    Sequence databases

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

    Genome annotation databases

    EnsembliENST00000342788; ENSP00000342235; ENSG00000178568. [Q15303-1]
    ENST00000402597; ENSP00000385565; ENSG00000178568. [Q15303-2]
    ENST00000436443; ENSP00000403204; ENSG00000178568. [Q15303-3]
    GeneIDi2066.
    KEGGihsa:2066.
    UCSCiuc002veg.1. human. [Q15303-1]
    uc002veh.1. human. [Q15303-3]
    uc010zji.1. human. [Q15303-2]
    uc010zjj.1. human. [Q15303-4]

    Polymorphism databases

    DMDMi3913590.

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Cross-referencesi

    Sequence databases

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

    3D structure databases

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

    Protein-protein interaction databases

    BioGridi 108378. 45 interactions.
    DIPi DIP-29650N.
    IntActi Q15303. 20 interactions.
    MINTi MINT-125091.
    STRINGi 9606.ENSP00000342235.

    Chemistry

    BindingDBi Q15303.
    ChEMBLi CHEMBL3009.
    GuidetoPHARMACOLOGYi 1799.

    PTM databases

    PhosphoSitei Q15303.

    Polymorphism databases

    DMDMi 3913590.

    Proteomic databases

    MaxQBi Q15303.
    PaxDbi Q15303.
    PRIDEi Q15303.

    Protocols and materials databases

    DNASUi 2066.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENST00000342788 ; ENSP00000342235 ; ENSG00000178568 . [Q15303-1 ]
    ENST00000402597 ; ENSP00000385565 ; ENSG00000178568 . [Q15303-2 ]
    ENST00000436443 ; ENSP00000403204 ; ENSG00000178568 . [Q15303-3 ]
    GeneIDi 2066.
    KEGGi hsa:2066.
    UCSCi uc002veg.1. human. [Q15303-1 ]
    uc002veh.1. human. [Q15303-3 ]
    uc010zji.1. human. [Q15303-2 ]
    uc010zjj.1. human. [Q15303-4 ]

    Organism-specific databases

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

    Phylogenomic databases

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

    Enzyme and pathway databases

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

    Miscellaneous databases

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

    Gene expression databases

    ArrayExpressi Q15303.
    Bgeei Q15303.
    CleanExi HS_ERBB4.
    Genevestigatori Q15303.

    Family and domain databases

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

    Publicationsi

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

    Entry informationi

    Entry nameiERBB4_HUMAN
    AccessioniPrimary (citable) accession number: Q15303
    Secondary accession number(s): B7ZLD7
    , B7ZLE2, B7ZLE3, Q2M1W1, Q59EW4
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: November 1, 1996
    Last modified: October 1, 2014
    This is version 168 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

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

    External Data

    Dasty 3