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Reviewed, UniProtKB/Swiss-Prot Q15303 (ERBB4_HUMAN)

Last modified July 7, 2009. Version 110. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents

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Names and origin

Protein namesRecommended name:
    Receptor tyrosine-protein kinase erbB-4
    EC=2.7.10.1
Alternative name(s):
    p180erbB4
    Tyrosine kinase-type cell surface receptor HER4
Gene names
Name: ERBB4
Synonyms: HER4
OrganismHomo sapiens (Human) [Complete proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

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Protein attributes

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

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General annotation (Comments)

Function

Specifically binds and is activated by neuregulins, NRG-2, NRG-3, heparin-binding EGF-like growth factor, betacellulin and NTAK. Interaction with these factors induces cell differentiation. Not activated by EGF, TGF-A, and amphiregulin.

Catalytic activity

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

Subunit structure

Homodimer or heterodimer with each of the other ERBB receptors Potential. Interacts with PDZ domains of DLG2, DLG3, DLG4 and the syntrophin SNTB2. Interacts with CBFA2T3, MUC1 and WWOX.

Subcellular location

Membrane; Single-pass type I membrane protein.

Tissue specificity

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

Domain

The WW-binding motifs mediate interaction with WWOX. Ref.7

Post-translational modification

Isoform JM-A is processed but not isoform JM-B. So, they respectively represent cleavable and non-cleavable forms of the receptor.

Ligand-binding increases phosphorylation on tyrosine residues.

Sequence similarities

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

Contains 1 protein kinase domain.

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Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]
Isoform JM-A (identifier: Q15303-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform JM-B (identifier: Q15303-2)

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

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

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Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2525 Potential
Chain26 – 13081283Receptor tyrosine-protein kinase erbB-4
PRO_0000016674

Regions

Topological domain26 – 651626Extracellular Potential
Transmembrane652 – 67524 Potential
Topological domain676 – 1308633Cytoplasmic Potential
Domain718 – 985268Protein kinase
Nucleotide binding724 – 7329ATP By similarity
Motif1032 – 10354WW-binding 1
Motif1298 – 13014WW-binding 2
Motif1306 – 13083PDZ-binding
Compositional bias186 – 334149Cys-rich
Compositional bias496 – 633138Cys-rich

Sites

Active site8431Proton acceptor By similarity
Binding site7511ATP By similarity

Amino acid modifications

Modified residue7331Phosphotyrosine Ref.9
Modified residue11621Phosphotyrosine; by autocatalysis By similarity
Modified residue11881Phosphotyrosine; by autocatalysis By similarity
Modified residue12581Phosphotyrosine; by autocatalysis By similarity
Modified residue12841Phosphotyrosine; by autocatalysis By similarity
Glycosylation1381N-linked (GlcNAc...) Ref.10
Glycosylation1741N-linked (GlcNAc...) Ref.10
Glycosylation1811N-linked (GlcNAc...) Potential
Glycosylation2531N-linked (GlcNAc...) Ref.10
Glycosylation3581N-linked (GlcNAc...) Ref.10
Glycosylation4101N-linked (GlcNAc...) Ref.10
Glycosylation4731N-linked (GlcNAc...) Ref.10
Glycosylation4951N-linked (GlcNAc...) Ref.10
Glycosylation5481N-linked (GlcNAc...) Potential
Glycosylation5761N-linked (GlcNAc...) Ref.10
Glycosylation6201N-linked (GlcNAc...) Potential
Disulfide bond29 ↔ 56 Ref.10
Disulfide bond156 ↔ 186 Ref.10
Disulfide bond189 ↔ 197 Ref.10
Disulfide bond193 ↔ 205 Ref.10
Disulfide bond213 ↔ 221 Ref.10
Disulfide bond217 ↔ 229 Ref.10
Disulfide bond230 ↔ 238 Ref.10
Disulfide bond234 ↔ 246 Ref.10
Disulfide bond249 ↔ 258 Ref.10
Disulfide bond262 ↔ 289 Ref.10
Disulfide bond293 ↔ 304 Ref.10
Disulfide bond308 ↔ 323 Ref.10
Disulfide bond326 ↔ 330 Ref.10
Disulfide bond503 ↔ 512 Ref.10
Disulfide bond507 ↔ 520 Ref.10
Disulfide bond523 ↔ 532 Ref.10
Disulfide bond536 ↔ 552 Ref.10
Disulfide bond555 ↔ 569 Ref.10
Disulfide bond559 ↔ 577 Ref.10
Disulfide bond580 ↔ 589 Ref.10
Disulfide bond593 ↔ 614 Ref.10
Disulfide bond617 ↔ 625 Ref.10
Disulfide bond621 ↔ 633 Ref.10

Natural variations

Alternative sequence626 – 64823NGPTS…LPQHA → IGSSIEDCIGLMD in isoform JM-B.
VSP_002895
Alternative sequence1046 – 106116Missing in isoform 3.
VSP_022148
Natural variant1401T → I in a colorectal adenocarcinoma sample; somatic mutation. Ref.11
VAR_042113
Natural variant3031S → Y in a lung squamous cell carcinoma sample; somatic mutation. Ref.11
VAR_042114

Experimental info

Mutagenesis10351Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1301. Ref.7
Mutagenesis13011Y → A: No effect on interaction with WWOX. Abolishes interaction with WWOX; when associated with A-1035. Ref.7

Secondary structure

1 ............................................................................................................................................................................ 1308
Helix Strand Turn

Details...

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Sequences

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

      1270       1280       1290       1300 
EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP YRHRNTVV

« Hide

Isoform JM-B.

Checksum: 346C1288AD041961
Show »

FASTA1,298145,578
Isoform 3.

Checksum: 60C0DFD446C7FA89
Show »

FASTA1,292145,198

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References

« Hide 'large scale' references
[1]"Ligand-specific activation of HER4/p180erbB4, a fourth member of the epidermal growth factor receptor family."
Plowman G.D., Culouscou J.-M., Whitney G.S., Green J.M., Carlton G.W., Foy L., Neubauer M.G., Shoyab M.
Proc. Natl. Acad. Sci. U.S.A. 90:1746-1750(1993) [PubMed: 8383326] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM JM-A).
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: 9334263] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS JM-A AND JM-B), 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: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM JM-A).
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 3).
Tissue: Brain.
[5]"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: 10725395] [Abstract]
Cited for: INTERACTION WITH DLG2; DLG3; DLG4 AND SNTB2.
[6]"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: 12939402] [Abstract]
Cited for: INTERACTION WITH MUC1.
[7]"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: 16061658] [Abstract]
Cited for: INTERACTION WITH WWOX, DOMAIN, MUTAGENESIS OF TYR-1035 AND TYR-1301.
[8]"ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression."
Linggi B., Carpenter G.
J. Biol. Chem. 281:25373-25380(2006) [PubMed: 16815842] [Abstract]
Cited for: INTERACTION WITH CBFA2T3.
[9]"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer."
Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. expand/collapse author list , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J.
Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-733, MASS SPECTROMETRY.
[10]"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: 16203964] [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.
[11]"Patterns of somatic mutation in human cancer genomes."
Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. expand/collapse author list , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.
Nature 446:153-158(2007) [PubMed: 17344846] [Abstract]
Cited for: VARIANTS [LARGE SCALE ANALYSIS] ILE-140 AND TYR-303.
+Additional computationally mapped references.

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Cross-references

Sequence databases

L07868 mRNA. Translation: AAB59446.1.
BC112199 mRNA. Translation: AAI12200.1.
AB209697 mRNA. Translation: BAD92934.1.
IPIIPI00016371.
IPI00215722.
IPI00816395.
PIRA47253.
RefSeqNP_001036064.1.
NP_005226.1.
UniGeneHs.390729

3D structure databases

EntryMethodResolution (Å)ChainPositionsPDBsum
2AHXX-ray2.40A/B26-641[»]
2R4BX-ray2.40A/B690-999[»]
3BBTX-ray2.80B/D702-1029[»]
3BBWX-ray4.00A/B702-1029[»]
3BCEX-ray2.50A/B/C702-1029[»]
ModBaseSearch...

Protein-protein interaction databases

DIPDIP:6094N.
IntActQ15303. 9 interactions.

PTM databases

PhosphoSiteQ15303.

Proteomic databases

PRIDEQ15303.

Genome annotation databases

EnsemblENSG00000178568. Homo sapiens. [Contig view]
GeneID2066.
KEGGhsa:2066.
UCSCuc002veg.1. human.
uc002veh.1. human.

Organism-specific databases

GeneCardsGC02M211955.
H-InvDBHIX0030012.
HGNCHGNC:3432. ERBB4.
HPACAB000276.
MIM600543. gene.
PharmGKBPA27847.
GenAtlasSearch...

Phylogenomic databases

HOGENOMQ15303.
HOVERGENQ15303.
OMAQ15303. CYADTIH.

Enzyme and pathway databases

BRENDA2.7.10.1. 247.

Gene expression databases

ArrayExpressQ15303.
BgeeQ15303.
CleanExHS_ERBB4.
GermOnlineENSG00000178568. Homo sapiens.

Family and domain databases

InterProIPR000494. EGF_rcpt_L.
IPR006211. Furin-like.
IPR006212. Furin_repeat.
IPR000719. Prot_kinase_core.
IPR017441. Protein_kinase_ATP_BS.
IPR016245. Tyr_kinase_rcpt_EGF/ERB/XmrK.
IPR001245. Tyr_pkinase.
IPR008266. Tyr_pkinase_AS.
IPR004019. YLP_motif.
[Graphical view]
PfamPF00757. Furin-like. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
PF01030. Recep_L_domain. 2 hits.
PF02757. YLP. 2 hits.
[Graphical view]
PIRSFPIRSF000619. TyrPK_EGF-R. 1 hit.
PRINTSPR00109. TYRKINASE.
ProDomPD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]
SMARTSM00261. FU. 5 hits.
SM00219. TyrKc. 1 hit.
[Graphical view]
PROSITEPS00107. PROTEIN_KINASE_ATP. 1 hit.
PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00109. PROTEIN_KINASE_TYR. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

NextBio8397.
PMAP-CutDBQ15303.
SOURCESearch...

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Entry information

Entry nameERBB4_HUMAN
AccessionPrimary (citable) accession number: Q15303
Secondary accession number(s): Q2M1W1, Q59EW4
Entry history
Integrated into UniProtKB/Swiss-Prot: December 15, 1998
Last sequence update: November 1, 1996
Last modified: July 7, 2009
This is version 110 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

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Index of Protein Data Bank (PDB) cross-references

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Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Binary interactions · Alternative products · Sequence annotation (Features) · Sequences · References · Cross-references · Entry information · Relevant documents