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Q61527

- ERBB4_MOUSE

UniProt

Q61527 - ERBB4_MOUSE

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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

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. receptor signaling protein tyrosine kinase activity Source: InterPro
  3. transcription regulatory region DNA binding Source: Ensembl
  4. 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
Complete GO annotation...

Keywords - Molecular functioni

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

Keywords - Biological processi

Apoptosis, Lactation, Transcription, Transcription regulation

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

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

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini26 – 652627ExtracellularSequence AnalysisAdd
BLAST
Transmembranei653 – 67321Sequence AnalysisAdd
BLAST
Topological domaini674 – 1308635CytoplasmicSequence AnalysisAdd
BLAST

GO - Cellular componenti

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

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

MaxQBiQ61527.
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.
ExpressionAtlasiQ61527. baseline and differential.
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...

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.
GeneTreeiENSGT00760000118799.
HOGENOMiHOG000230982.
HOVERGENiHBG000490.
InParanoidiQ61527.
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

        10         20         30         40         50
MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR
60 70 80 90 100
KYYENCEVVM GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE
110 120 130 140 150
NLRIIRGTKL YEDRYALAIF LNYRKDGNFG LQELGLKNLT EILNGGVYVD
160 170 180 190 200
QNKFLCYADT IHWQDIVRNP WPSNMTLVST NGSSGCGRCH KSCTGRCWGP
210 220 230 240 250
TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG PKDTDCFACM
260 270 280 290 300
NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD
310 320 330 340 350
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS
360 370 380 390 400
SNIDKFINCT KINGNLIFLV TGIHGDPYNA IDAIDPEKLN VFRTVREITG
410 420 430 440 450
FLNIQSWPPN MTDFSVFSNL VTIGGRVLYS GLSLLILKQQ GITSLQFQSL
460 470 480 490 500
KEISAGNIYI TDNSNLCYYH TINWTTLFST INQRIVIRDN RRAENCTAEG
510 520 530 540 550
MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD GEFREFENGS
560 570 580 590 600
ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA
610 620 630 640 650
NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART
660 670 680 690 700
PLIAAGVIGG LFILVIMALT FAVYVRRKSI KKKRALRRFL ETELVEPLTP
710 720 730 740 750
SGTAPNQAQL RILKETELKR VKVLGSGAFG TVYKGIWVPE GETVKIPVAI
760 770 780 790 800
KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP TIQLVTQLMP
810 820 830 840 850
HGCLLDYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV HRDLAARNVL
860 870 880 890 900
VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ
910 920 930 940 950
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY
960 970 980 990 1000
MVMVKCWMID ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND
1010 1020 1030 1040 1050
SKFFQNLLDE EDLEDMMDAE EYLVPQAFNI PPPIYTSRTR IDSNRSEIGH
1060 1070 1080 1090 1100
SPPPAYTPMS GNQFVYQDGG FATQQGMPMP YRATTSTIPE APVAQGATAE
1110 1120 1130 1140 1150
MFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERN PRGELDEEGY
1160 1170 1180 1190 1200
MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED
1210 1220 1230 1240 1250
EYVNEPLYLN TFANALGSAE YMKNSVLSVP EKAKKAFDNP DYWNHSLPPR
1260 1270 1280 1290 1300
STLQHPDYLQ EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP

YRHRNTVV

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:
EMBLi
GenBanki
DDBJi
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:
EMBLi
GenBanki
DDBJi
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

MaxQBi Q61527.
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 ENSGT00760000118799.
HOGENOMi HOG000230982.
HOVERGENi HBG000490.
InParanoidi Q61527.
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

ChiTaRSi Erbb4. mouse.
NextBioi 284772.
PROi Q61527.
SOURCEi Search...

Gene expression databases

Bgeei Q61527.
ExpressionAtlasi Q61527. baseline and differential.
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

« Hide 'large scale' publications
  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: November 26, 2014
This is version 138 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