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Q61527

- ERBB4_MOUSE

UniProt

Q61527 - ERBB4_MOUSE

Protein

Receptor tyrosine-protein kinase erbB-4

Gene

Erbb4

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 136 (01 Oct 2014)
      Sequence version 5 (25 Jan 2012)
      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.8 Publications

    Catalytic activityi

    ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-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+ By similarity.By similarity

    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. protein binding Source: IntAct
    3. receptor signaling protein tyrosine kinase activity Source: InterPro
    4. transcription regulatory region DNA binding Source: Ensembl
    5. transmembrane receptor protein tyrosine kinase activity Source: UniProtKB

    GO - Biological processi

    1. cardiac muscle tissue regeneration Source: UniProtKB
    2. cell fate commitment Source: MGI
    3. cell migration Source: UniProtKB
    4. central nervous system morphogenesis Source: UniProtKB
    5. embryonic pattern specification Source: UniProtKB
    6. heart development Source: MGI
    7. lactation Source: UniProtKB
    8. mammary gland alveolus development Source: UniProtKB
    9. mammary gland epithelial cell differentiation Source: UniProtKB
    10. mitochondrial fragmentation involved in apoptotic process Source: UniProtKB
    11. negative regulation of apoptotic process Source: UniProtKB
    12. negative regulation of cell proliferation Source: UniProtKB
    13. nervous system development Source: MGI
    14. neural crest cell migration Source: UniProtKB
    15. olfactory bulb interneuron differentiation Source: UniProtKB
    16. peptidyl-tyrosine phosphorylation Source: UniProtKB
    17. positive regulation of cardiac muscle cell proliferation Source: UniProtKB
    18. positive regulation of cell proliferation Source: UniProtKB
    19. positive regulation of ERK1 and ERK2 cascade Source: UniProtKB
    20. positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
    21. positive regulation of STAT protein import into nucleus Source: UniProtKB
    22. positive regulation of transcription, DNA-templated Source: UniProtKB
    23. positive regulation of tyrosine phosphorylation of Stat5 protein Source: UniProtKB
    24. protein autophosphorylation Source: UniProtKB
    25. regulation of cell migration Source: UniProtKB
    26. transcription, DNA-templated Source: UniProtKB-KW
    27. 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

    ReactomeiREACT_188191. Signaling by ERBB2.
    REACT_188528. GRB2 events in ERBB2 signaling.
    REACT_188574. SHC1 events in ERBB2 signaling.
    REACT_188579. Signaling by ERBB4.
    REACT_188580. SHC1 events in ERBB4 signaling.
    REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_198574. Nuclear signaling by ERBB4.
    REACT_199100. Downregulation of ERBB4 signaling.
    REACT_203296. PI3K events in ERBB4 signaling.
    REACT_215348. PI3K events in ERBB2 signaling.
    REACT_226341. PIP3 activates AKT signaling.

    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
    Cleaved into the following chain:
    ERBB4 intracellular domain
    Short name:
    4ICD
    Short name:
    E4ICD
    Alternative name(s):
    s80HER4
    Gene namesi
    Name:Erbb4
    Synonyms:Mer4
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 1

    Organism-specific databases

    MGIiMGI:104771. Erbb4.

    Subcellular locationi

    Cell membrane 1 Publication; Single-pass type I membrane protein 1 Publication
    Note: In response to NRG1 treatment, the activated receptor is internalized.
    Chain ERBB4 intracellular domain : Nucleus. Mitochondrion By similarity
    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 By similarity.By similarity

    GO - Cellular componenti

    1. basolateral plasma membrane Source: Ensembl
    2. integral component of membrane Source: UniProtKB-KW
    3. mitochondrion Source: UniProtKB-SubCell
    4. nucleus Source: UniProtKB-SubCell
    5. receptor complex Source: MGI

    Keywords - Cellular componenti

    Cell membrane, Membrane, Mitochondrion, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Embryonically lethal. Embryos die at about 10 dpc, due to defects in the development of myocardial trabeculae in the heart ventricle that lead to severely reduced embryonic blood flow. Mice also display aberrant innervation from and to the hindbrain, especially concerning the trigeminal, facial and acoustic ganglia. This is due to aberrant migration of a subpopulation of cranial neural crest cells.4 Publications

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Signal peptidei1 – 2525Sequence AnalysisAdd
    BLAST
    Chaini26 – 13081283Receptor tyrosine-protein kinase erbB-4PRO_0000270146Add
    BLAST
    Chaini676 – 1308633ERBB4 intracellular domainPRO_0000396798Add
    BLAST

    Amino acid modifications

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Disulfide bondi29 ↔ 56By similarity
    Glycosylationi138 – 1381N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi156 ↔ 186By similarity
    Glycosylationi174 – 1741N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi181 – 1811N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi189 ↔ 197By similarity
    Disulfide bondi193 ↔ 205By similarity
    Disulfide bondi213 ↔ 221By similarity
    Disulfide bondi217 ↔ 229By similarity
    Disulfide bondi230 ↔ 238By similarity
    Disulfide bondi234 ↔ 246By similarity
    Disulfide bondi249 ↔ 258By similarity
    Glycosylationi253 – 2531N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi262 ↔ 289By similarity
    Disulfide bondi293 ↔ 304By similarity
    Disulfide bondi308 ↔ 323By similarity
    Disulfide bondi326 ↔ 330By similarity
    Glycosylationi410 – 4101N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi473 – 4731N-linked (GlcNAc...)Sequence Analysis
    Glycosylationi495 – 4951N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi503 ↔ 512By similarity
    Disulfide bondi507 ↔ 520By similarity
    Disulfide bondi523 ↔ 532By similarity
    Disulfide bondi536 ↔ 552By similarity
    Glycosylationi548 – 5481N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi555 ↔ 569By similarity
    Disulfide bondi559 ↔ 577By similarity
    Glycosylationi576 – 5761N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi580 ↔ 589By similarity
    Disulfide bondi593 ↔ 614By similarity
    Disulfide bondi617 ↔ 625By similarity
    Glycosylationi620 – 6201N-linked (GlcNAc...)Sequence Analysis
    Disulfide bondi621 ↔ 633By similarity
    Modified residuei875 – 8751Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1035 – 10351Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1056 – 10561Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1150 – 11501Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1162 – 11621Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1188 – 11881Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1202 – 12021Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1242 – 12421Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1258 – 12581Phosphotyrosine; by autocatalysisBy similarity
    Modified residuei1284 – 12841Phosphotyrosine; by autocatalysisBy similarity

    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 By similarity.By similarity
    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 By similarity.By similarity
    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 By similarity.By similarity

    Keywords - PTMi

    Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

    Proteomic databases

    PaxDbiQ61527.
    PRIDEiQ61527.

    Expressioni

    Tissue specificityi

    Isoform JM-A CYT-2 and isoform JM-B CYT-2 are expressed in cerebellum, cerebral cortex, spinal cord, medulla oblongata and eye, but the kidney expresses solely isoform JM-A CYT-2 and the heart solely isoform JM-B CYT-2.1 Publication

    Gene expression databases

    BgeeiQ61527.
    GenevestigatoriQ61527.

    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 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 BCL2. Interacts (phosphorylated) with STAT1 By similarity. Interacts with CBFA2T3. Interacts (soluble intracellular domain) with STAT5A.By similarity2 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    WWOXQ9NZC73EBI-4398741,EBI-4320739From a different organism.

    Protein-protein interaction databases

    DIPiDIP-29887N.
    IntActiQ61527. 2 interactions.
    STRINGi10090.ENSMUSP00000112713.

    Structurei

    3D structure databases

    ProteinModelPortaliQ61527.
    SMRiQ61527. Positions 26-639, 642-1026.
    ModBaseiSearch...
    MobiDBiSearch...

    Topological domain

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Topological domaini26 – 652627ExtracellularSequence AnalysisAdd
    BLAST
    Topological domaini674 – 1308635CytoplasmicSequence AnalysisAdd
    BLAST

    Transmembrane

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transmembranei653 – 67321Sequence 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 signalBy similarity
    Motifi1032 – 10354PPxy motif 1By similarity
    Motifi1282 – 12854PPxY motif 2By similarity
    Motifi1290 – 12923PDZ-bindingBy similarity

    Compositional bias

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Compositional biasi186 – 26277Cys-richAdd
    BLAST
    Compositional biasi496 – 59398Cys-richAdd
    BLAST
    Compositional biasi1281 – 12844Poly-Pro

    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.
    GeneTreeiENSGT00600000084253.
    HOGENOMiHOG000230982.
    HOVERGENiHBG000490.
    InParanoidiB2KGF6.
    KOiK05085.
    OMAiRTRIDSN.
    OrthoDBiEOG7V49XM.
    PhylomeDBiQ61527.
    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 (3)i

    Sequence statusi: Complete.

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

    This entry describes 3 isoformsi produced by alternative splicing. Align

    Note: Additional isoforms seem to exist.

    Isoform JM-A CYT-1 (identifier: Q61527-1) [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

    MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR     50
    KYYENCEVVM GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE 100
    NLRIIRGTKL YEDRYALAIF LNYRKDGNFG LQELGLKNLT EILNGGVYVD 150
    QNKFLCYADT IHWQDIVRNP WPSNMTLVST NGSSGCGRCH KSCTGRCWGP 200
    TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG PKDTDCFACM 250
    NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD 300
    SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS 350
    SNIDKFINCT KINGNLIFLV TGIHGDPYNA IDAIDPEKLN VFRTVREITG 400
    FLNIQSWPPN MTDFSVFSNL VTIGGRVLYS GLSLLILKQQ GITSLQFQSL 450
    KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RRAENCTAEG 500
    MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD GEFREFENGS 550
    ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 600
    NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART 650
    PLIAAGVIGG LFILVIMALT FAVYVRRKSI KKKRALRRFL ETELVEPLTP 700
    SGTAPNQAQL RILKETELKR VKVLGSGAFG TVYKGIWVPE GETVKIPVAI 750
    KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP TIQLVTQLMP 800
    HGCLLDYVHE 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 PPPIYTSRTR IDSNRSEIGH 1050
    SPPPAYTPMS GNQFVYQDGG FATQQGMPMP YRATTSTIPE APVAQGATAE 1100
    MFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERN PRGELDEEGY 1150
    MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED 1200
    EYVNEPLYLN TFANALGSAE YMKNSVLSVP EKAKKAFDNP DYWNHSLPPR 1250
    STLQHPDYLQ EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP 1300
    YRHRNTVV 1308

    Note: Proteolytical processing generates E4ICD1 (s80Cyt1).

    Length:1,308
    Mass (Da):146,855
    Last modified:January 25, 2012 - v5
    Checksum:i65943278A7E7F2F6
    GO
    Isoform JM-B CYT-2 (identifier: Q61527-2) [UniParc]FASTAAdd to Basket

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

    Show »
    Length:1,298
    Mass (Da):145,595
    Checksum:i22EF9A9BE932C0F7
    GO
    Isoform JM-A CYT-2 (identifier: Q61527-3) [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):145,245
    Checksum:i46FBDC6AE4D69E08
    GO

    Experimental Info

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Sequence conflicti1019 – 10191A → V in AAC28334. 1 PublicationCurated

    Alternative sequence

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Alternative sequencei626 – 64823NGPTS…LPQHA → IGSSIEDCIGLTD in isoform JM-B CYT-2. 1 PublicationVSP_002896Add
    BLAST
    Alternative sequencei1046 – 106116Missing in isoform JM-A CYT-2. 1 PublicationVSP_042131Add
    BLAST

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    CU368746
    , CU372923, CU392849, CU405881, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ51554.1.
    CU368746
    , CU372923, CU392849, CU405881, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ51555.1.
    CU392849
    , CU368746, CU372923, CU405881, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ51831.1.
    CU459207
    , CU368746, CU372923, CU392849, CU405881, CU407006, CU459008 Genomic DNA. Translation: CAQ51899.1.
    CU392849
    , CU368746, CU372923, CU405881, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ51832.1.
    CU459207
    , CU368746, CU372923, CU392849, CU405881, CU407006, CU459008 Genomic DNA. Translation: CAQ51900.1.
    CU405881
    , CU368746, CU372923, CU392849, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ52134.1.
    CU405881
    , CU368746, CU372923, CU392849, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ52135.1.
    CU459008
    , CU368746, CU372923, CU392849, CU405881, CU407006, CU459207 Genomic DNA. Translation: CAQ52171.1.
    CU459008
    , CU368746, CU372923, CU392849, CU405881, CU407006, CU459207 Genomic DNA. Translation: CAQ52172.1.
    CU407006
    , CU368746, CU372923, CU392849, CU405881, CU459008, CU459207 Genomic DNA. Translation: CAQ52191.1.
    CU407006
    , CU368746, CU372923, CU392849, CU405881, CU459008, CU459207 Genomic DNA. Translation: CAQ52192.1.
    CU372923
    , CU368746, CU392849, CU405881, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ52287.1.
    CU372923
    , CU368746, CU392849, CU405881, CU407006, CU459008, CU459207 Genomic DNA. Translation: CAQ52288.1.
    AK144050 mRNA. Translation: BAE25671.1.
    L47241 mRNA. Translation: AAA93534.1.
    AF059177 mRNA. Translation: AAC28334.1.
    CCDSiCCDS48285.1. [Q61527-3]
    RefSeqiNP_034284.1. NM_010154.1. [Q61527-3]
    XP_006495755.1. XM_006495692.1. [Q61527-1]
    XP_006495756.1. XM_006495693.1. [Q61527-2]
    XP_006536970.1. XM_006536907.1. [Q61527-1]
    UniGeneiMm.442420.

    Genome annotation databases

    EnsembliENSMUST00000119142; ENSMUSP00000112713; ENSMUSG00000062209. [Q61527-1]
    ENSMUST00000121473; ENSMUSP00000114123; ENSMUSG00000062209. [Q61527-3]
    GeneIDi13869.
    KEGGimmu:13869.
    UCSCiuc007bjb.1. mouse. [Q61527-3]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    CU368746
    , CU372923 , CU392849 , CU405881 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ51554.1 .
    CU368746
    , CU372923 , CU392849 , CU405881 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ51555.1 .
    CU392849
    , CU368746 , CU372923 , CU405881 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ51831.1 .
    CU459207
    , CU368746 , CU372923 , CU392849 , CU405881 , CU407006 , CU459008 Genomic DNA. Translation: CAQ51899.1 .
    CU392849
    , CU368746 , CU372923 , CU405881 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ51832.1 .
    CU459207
    , CU368746 , CU372923 , CU392849 , CU405881 , CU407006 , CU459008 Genomic DNA. Translation: CAQ51900.1 .
    CU405881
    , CU368746 , CU372923 , CU392849 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ52134.1 .
    CU405881
    , CU368746 , CU372923 , CU392849 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ52135.1 .
    CU459008
    , CU368746 , CU372923 , CU392849 , CU405881 , CU407006 , CU459207 Genomic DNA. Translation: CAQ52171.1 .
    CU459008
    , CU368746 , CU372923 , CU392849 , CU405881 , CU407006 , CU459207 Genomic DNA. Translation: CAQ52172.1 .
    CU407006
    , CU368746 , CU372923 , CU392849 , CU405881 , CU459008 , CU459207 Genomic DNA. Translation: CAQ52191.1 .
    CU407006
    , CU368746 , CU372923 , CU392849 , CU405881 , CU459008 , CU459207 Genomic DNA. Translation: CAQ52192.1 .
    CU372923
    , CU368746 , CU392849 , CU405881 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ52287.1 .
    CU372923
    , CU368746 , CU392849 , CU405881 , CU407006 , CU459008 , CU459207 Genomic DNA. Translation: CAQ52288.1 .
    AK144050 mRNA. Translation: BAE25671.1 .
    L47241 mRNA. Translation: AAA93534.1 .
    AF059177 mRNA. Translation: AAC28334.1 .
    CCDSi CCDS48285.1. [Q61527-3 ]
    RefSeqi NP_034284.1. NM_010154.1. [Q61527-3 ]
    XP_006495755.1. XM_006495692.1. [Q61527-1 ]
    XP_006495756.1. XM_006495693.1. [Q61527-2 ]
    XP_006536970.1. XM_006536907.1. [Q61527-1 ]
    UniGenei Mm.442420.

    3D structure databases

    ProteinModelPortali Q61527.
    SMRi Q61527. Positions 26-639, 642-1026.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    DIPi DIP-29887N.
    IntActi Q61527. 2 interactions.
    STRINGi 10090.ENSMUSP00000112713.

    Proteomic databases

    PaxDbi Q61527.
    PRIDEi Q61527.

    Protocols and materials databases

    DNASUi 13869.
    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000119142 ; ENSMUSP00000112713 ; ENSMUSG00000062209 . [Q61527-1 ]
    ENSMUST00000121473 ; ENSMUSP00000114123 ; ENSMUSG00000062209 . [Q61527-3 ]
    GeneIDi 13869.
    KEGGi mmu:13869.
    UCSCi uc007bjb.1. mouse. [Q61527-3 ]

    Organism-specific databases

    CTDi 2066.
    MGIi MGI:104771. Erbb4.

    Phylogenomic databases

    eggNOGi COG0515.
    GeneTreei ENSGT00600000084253.
    HOGENOMi HOG000230982.
    HOVERGENi HBG000490.
    InParanoidi B2KGF6.
    KOi K05085.
    OMAi RTRIDSN.
    OrthoDBi EOG7V49XM.
    PhylomeDBi Q61527.
    TreeFami TF106002.

    Enzyme and pathway databases

    Reactomei REACT_188191. Signaling by ERBB2.
    REACT_188528. GRB2 events in ERBB2 signaling.
    REACT_188574. SHC1 events in ERBB2 signaling.
    REACT_188579. Signaling by ERBB4.
    REACT_188580. SHC1 events in ERBB4 signaling.
    REACT_196588. Constitutive PI3K/AKT Signaling in Cancer.
    REACT_198574. Nuclear signaling by ERBB4.
    REACT_199100. Downregulation of ERBB4 signaling.
    REACT_203296. PI3K events in ERBB4 signaling.
    REACT_215348. PI3K events in ERBB2 signaling.
    REACT_226341. PIP3 activates AKT signaling.

    Miscellaneous databases

    NextBioi 284772.
    PROi Q61527.
    SOURCEi Search...

    Gene expression databases

    Bgeei Q61527.
    Genevestigatori Q61527.

    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. Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
      Strain: C57BL/6J.
    2. "The transcriptional landscape of the mammalian genome."
      Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
      , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
      Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1263 (JM-A CYT-2).
      Strain: C57BL/6J.
      Tissue: Kidney.
    3. "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] OF 624-650 (ISOFORMS JM-A CYT-2 AND JM-B CYT-2).
      Tissue: Heart and Kidney.
    4. "Synapse-associated expression of an acetylcholine receptor-inducing protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3, in developing mammalian muscle."
      Moscoso L.M., Chu G.C., Gautam M., Noakes P.G., Merlie J.P., Sanes J.R.
      Dev. Biol. 172:158-169(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1019-1102 (ISOFORM JM-A CYT-1).
      Strain: C57BL/6.
      Tissue: Brain.
    5. "Potential signaling network by EGF-like growth factors in the mouse uterus during early pregnancy."
      Lim H., Das S.K., Dey S.K.
      Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases
      Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1019-1093 (ISOFORM JM-A CYT-1).
      Strain: CD-1.
      Tissue: Uterus.
    6. "Aberrant neural and cardiac development in mice lacking the ErbB4 neuregulin receptor."
      Gassmann M., Casagranda F., Orioli D., Simon H., Lai C., Klein R., Lemke G.
      Nature 378:390-394(1995) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE, FUNCTION.
    7. "ErbB4 signaling in the mammary gland is required for lobuloalveolar development and Stat5 activation during lactation."
      Jones F.E., Welte T., Fu X.Y., Stern D.F.
      J. Cell Biol. 147:77-88(1999) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN MAMMARY GLAND DEVELOPMENT AND ACTIVATION OF STAT5A, INTERACTION WITH STAT5A.
    8. "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, TISSUE SPECIFICITY.
    9. "Defects in pathfinding by cranial neural crest cells in mice lacking the neuregulin receptor ErbB4."
      Golding J.P., Trainor P., Krumlauf R., Gassmann M.
      Nat. Cell Biol. 2:103-109(2000) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE, FUNCTION.
    10. "Impaired differentiation and lactational failure of Erbb4-deficient mammary glands identify ERBB4 as an obligate mediator of STAT5."
      Long W., Wagner K.U., Lloyd K.C., Binart N., Shillingford J.M., Hennighausen L., Jones F.E.
      Development 130:5257-5268(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    11. "Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality."
      Tidcombe H., Jackson-Fisher A., Mathers K., Stern D.F., Gassmann M., Golding J.P.
      Proc. Natl. Acad. Sci. U.S.A. 100:8281-8286(2003) [PubMed] [Europe PMC] [Abstract]
      Cited for: DISRUPTION PHENOTYPE.
    12. "Receptor tyrosine kinase ErbB4 modulates neuroblast migration and placement in the adult forebrain."
      Anton E.S., Ghashghaei H.T., Weber J.L., McCann C., Fischer T.M., Cheung I.D., Gassmann M., Messing A., Klein R., Schwab M.H., Lloyd K.C., Lai C.
      Nat. Neurosci. 7:1319-1328(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION IN NEUROBLAST MIGRATION.
    13. "ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events."
      Clark D.E., Williams C.C., Duplessis T.T., Moring K.L., Notwick A.R., Long W., Lane W.S., Beuvink I., Hynes N.E., Jones F.E.
      J. Biol. Chem. 280:24175-24180(2005) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    14. "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.
    15. "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, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION.
    16. "ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and exert opposing effects on the mammary epithelium in vivo."
      Muraoka-Cook R.S., Sandahl M.A., Strunk K.E., Miraglia L.C., Husted C., Hunter D.M., Elenius K., Chodosh L.A., Earp H.S. III
      Mol. Cell. Biol. 29:4935-4948(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION OF E4ICD.
    17. "Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and repair of heart injury."
      Bersell K., Arab S., Haring B., Kuhn B.
      Cell 138:257-270(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION AS NRG1 RECEPTOR IN POSTNATAL CARDIOMYOCYTE PROLIFERATION.
    18. "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.
    19. "Neuregulin signaling, cortical circuitry development and schizophrenia."
      Rico B., Marin O.
      Curr. Opin. Genet. Dev. 21:262-270(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: REVIEW ON ROLE AS NEUREGULIN RECEPTOR.

    Entry informationi

    Entry nameiERBB4_MOUSE
    AccessioniPrimary (citable) accession number: Q61527
    Secondary accession number(s): B2KGF5
    , B2KGF6, O88460, Q3UNS6
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: December 15, 1998
    Last sequence update: January 25, 2012
    Last modified: October 1, 2014
    This is version 136 of the entry and version 5 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Keywords - Technical termi

    Complete proteome, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. Human and mouse protein kinases
      Human and mouse protein kinases: classification and index
    3. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3