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Receptor tyrosine-protein kinase erbB-4 (EC 2.7.10.1) (Proto-oncogene-like protein c-ErbB-4) [Cleaved into: ERBB4 intracellular domain (4ICD) (E4ICD) (s80HER4)]

 ERBB4_MOUSE             Reviewed;        1308 AA.
Q61527; B2KGF5; B2KGF6; O88460; Q3UNS6;
15-DEC-1998, integrated into UniProtKB/Swiss-Prot.
25-JAN-2012, sequence version 5.
03-JUL-2019, entry version 177.
RecName: Full=Receptor tyrosine-protein kinase erbB-4;
EC=2.7.10.1;
AltName: Full=Proto-oncogene-like protein c-ErbB-4;
Contains:
RecName: Full=ERBB4 intracellular domain;
Short=4ICD;
Short=E4ICD;
AltName: Full=s80HER4;
Flags: Precursor;
Name=Erbb4; Synonyms=Mer4;
Mus musculus (Mouse).
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
Muroidea; Muridae; Murinae; Mus; Mus.
NCBI_TaxID=10090;
[1]
NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
STRAIN=C57BL/6J;
PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S.,
She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W.,
Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T.,
Zhou S., Teague B., Potamousis K., Churas C., Place M., Herschleb J.,
Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z.,
Lindblad-Toh K., Eichler E.E., Ponting C.P.;
"Lineage-specific biology revealed by a finished genome assembly of
the mouse.";
PLoS Biol. 7:E1000112-E1000112(2009).
[2]
NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1263 (JM-A CYT-2).
STRAIN=C57BL/6J; TISSUE=Kidney;
PubMed=16141072; DOI=10.1126/science.1112014;
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.;
"The transcriptional landscape of the mammalian genome.";
Science 309:1559-1563(2005).
[3]
NUCLEOTIDE SEQUENCE [MRNA] OF 624-650 (ISOFORMS JM-A CYT-2 AND JM-B
CYT-2).
TISSUE=Heart, and Kidney;
PubMed=9334263; DOI=10.1074/jbc.272.42.26761;
Elenius K., Corfas G., Paul S., Choi C.J., Rio C., Plowman G.D.,
Klagsbrun M.;
"A novel juxtamembrane domain isoform of HER4/ErbB4. Isoform-specific
tissue distribution and differential processing in response to phorbol
ester.";
J. Biol. Chem. 272:26761-26768(1997).
[4]
NUCLEOTIDE SEQUENCE [MRNA] OF 1019-1102 (ISOFORM JM-A CYT-1).
STRAIN=C57BL/6J; TISSUE=Brain;
PubMed=7589796; DOI=10.1006/dbio.1995.0012;
Moscoso L.M., Chu G.C., Gautam M., Noakes P.G., Merlie J.P.,
Sanes J.R.;
"Synapse-associated expression of an acetylcholine receptor-inducing
protein, ARIA/heregulin, and its putative receptors, ErbB2 and ErbB3,
in developing mammalian muscle.";
Dev. Biol. 172:158-169(1995).
[5]
NUCLEOTIDE SEQUENCE [MRNA] OF 1019-1093 (ISOFORM JM-A CYT-1).
STRAIN=CD-1; TISSUE=Uterus;
Lim H., Das S.K., Dey S.K.;
"Potential signaling network by EGF-like growth factors in the mouse
uterus during early pregnancy.";
Submitted (APR-1998) to the EMBL/GenBank/DDBJ databases.
[6]
DISRUPTION PHENOTYPE, AND FUNCTION.
PubMed=7477376; DOI=10.1038/378390a0;
Gassmann M., Casagranda F., Orioli D., Simon H., Lai C., Klein R.,
Lemke G.;
"Aberrant neural and cardiac development in mice lacking the ErbB4
neuregulin receptor.";
Nature 378:390-394(1995).
[7]
FUNCTION IN MAMMARY GLAND DEVELOPMENT AND ACTIVATION OF STAT5A, AND
INTERACTION WITH STAT5A.
PubMed=10508857; DOI=10.1083/jcb.147.1.77;
Jones F.E., Welte T., Fu X.Y., Stern D.F.;
"ErbB4 signaling in the mammary gland is required for lobuloalveolar
development and Stat5 activation during lactation.";
J. Cell Biol. 147:77-88(1999).
[8]
ALTERNATIVE SPLICING, AND TISSUE SPECIFICITY.
PubMed=10353604; DOI=10.1038/sj.onc.1202612;
Elenius K., Choi C.J., Paul S., Santiestevan E., Nishi E.,
Klagsbrun M.;
"Characterization of a naturally occurring ErbB4 isoform that does not
bind or activate phosphatidyl inositol 3-kinase.";
Oncogene 18:2607-2615(1999).
[9]
DISRUPTION PHENOTYPE, AND FUNCTION.
PubMed=10655590; DOI=10.1038/35000058;
Golding J.P., Trainor P., Krumlauf R., Gassmann M.;
"Defects in pathfinding by cranial neural crest cells in mice lacking
the neuregulin receptor ErbB4.";
Nat. Cell Biol. 2:103-109(2000).
[10]
DISRUPTION PHENOTYPE.
PubMed=12954715; DOI=10.1242/dev.00715;
Long W., Wagner K.U., Lloyd K.C., Binart N., Shillingford J.M.,
Hennighausen L., Jones F.E.;
"Impaired differentiation and lactational failure of Erbb4-deficient
mammary glands identify ERBB4 as an obligate mediator of STAT5.";
Development 130:5257-5268(2003).
[11]
DISRUPTION PHENOTYPE.
PubMed=12824469; DOI=10.1073/pnas.1436402100;
Tidcombe H., Jackson-Fisher A., Mathers K., Stern D.F., Gassmann M.,
Golding J.P.;
"Neural and mammary gland defects in ErbB4 knockout mice genetically
rescued from embryonic lethality.";
Proc. Natl. Acad. Sci. U.S.A. 100:8281-8286(2003).
[12]
FUNCTION IN NEUROBLAST MIGRATION.
PubMed=15543145; DOI=10.1038/nn1345;
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.;
"Receptor tyrosine kinase ErbB4 modulates neuroblast migration and
placement in the adult forebrain.";
Nat. Neurosci. 7:1319-1328(2004).
[13]
FUNCTION.
PubMed=15863494; DOI=10.1074/jbc.M414044200;
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.;
"ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating
novel STAT5A serine phosphorylation events.";
J. Biol. Chem. 280:24175-24180(2005).
[14]
INTERACTION WITH CBFA2T3.
PubMed=16815842; DOI=10.1074/jbc.M603998200;
Linggi B., Carpenter G.;
"ErbB-4 s80 intracellular domain abrogates ETO2-dependent
transcriptional repression.";
J. Biol. Chem. 281:25373-25380(2006).
[15]
FUNCTION, PROTEOLYTIC PROCESSING, AND SUBCELLULAR LOCATION.
PubMed=16837552; DOI=10.1091/mbc.E06-02-0101;
Muraoka-Cook R.S., Sandahl M., Husted C., Hunter D., Miraglia L.,
Feng S.M., Elenius K., Earp H.S. III;
"The intracellular domain of ErbB4 induces differentiation of mammary
epithelial cells.";
Mol. Biol. Cell 17:4118-4129(2006).
[16]
FUNCTION OF E4ICD.
PubMed=19596786; DOI=10.1128/MCB.01705-08;
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;
"ErbB4 splice variants Cyt1 and Cyt2 differ by 16 amino acids and
exert opposing effects on the mammary epithelium in vivo.";
Mol. Cell. Biol. 29:4935-4948(2009).
[17]
FUNCTION AS NRG1 RECEPTOR IN POSTNATAL CARDIOMYOCYTE PROLIFERATION.
PubMed=19632177; DOI=10.1016/j.cell.2009.04.060;
Bersell K., Arab S., Haring B., Kuhn B.;
"Neuregulin1/ErbB4 signaling induces cardiomyocyte proliferation and
repair of heart injury.";
Cell 138:257-270(2009).
[18]
REVIEW.
PubMed=14504474;
Jones F.E., Golding J.P., Gassmann M.;
"ErbB4 signaling during breast and neural development: novel genetic
models reveal unique ErbB4 activities.";
Cell Cycle 2:555-559(2003).
[19]
IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
TISSUE=Brain;
PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
"A tissue-specific atlas of mouse protein phosphorylation and
expression.";
Cell 143:1174-1189(2010).
[20]
REVIEW ON ROLE AS NEUREGULIN RECEPTOR.
PubMed=21295966; DOI=10.1016/j.gde.2010.12.010;
Rico B., Marin O.;
"Neuregulin signaling, cortical circuitry development and
schizophrenia.";
Curr. Opin. Genet. Dev. 21:262-270(2011).
-!- FUNCTION: Tyrosine-protein kinase that plays an essential role as
cell surface receptor for neuregulins and EGF family members and
regulates development of the heart, the central nervous system and
the mammary gland, gene transcription, cell proliferation,
differentiation, migration and apoptosis. Required for normal
cardiac muscle differentiation during embryonic development, and
for postnatal cardiomyocyte proliferation. Required for normal
development of the embryonic central nervous system, especially
for normal neural crest cell migration and normal axon guidance.
Required for mammary gland differentiation, induction of milk
proteins and lactation. Acts as cell-surface receptor for the
neuregulins NRG1, NRG2, NRG3 and NRG4 and the EGF family members
BTC, EREG and HBEGF. Ligand binding triggers receptor dimerization
and autophosphorylation at specific tyrosine residues that then
serve as binding sites for scaffold proteins and effectors. Ligand
specificity and signaling is modulated by alternative splicing,
proteolytic processing, and by the formation of heterodimers with
other ERBB family members, thereby creating multiple combinations
of intracellular phosphotyrosines that trigger ligand- and
context-specific cellular responses. Mediates phosphorylation of
SHC1 and activation of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1.
Isoform JM-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. {ECO:0000269|PubMed:10508857,
ECO:0000269|PubMed:10655590, ECO:0000269|PubMed:15543145,
ECO:0000269|PubMed:15863494, ECO:0000269|PubMed:16837552,
ECO:0000269|PubMed:19596786, ECO:0000269|PubMed:19632177,
ECO:0000269|PubMed:7477376}.
-!- CATALYTIC ACTIVITY:
Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-
tyrosyl-[protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136,
Rhea:RHEA-COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
ChEBI:CHEBI:46858, ChEBI:CHEBI:82620, ChEBI:CHEBI:456216;
EC=2.7.10.1; Evidence={ECO:0000255|PROSITE-ProRule:PRU10028};
-!- ACTIVITY REGULATION: Binding of a cognate ligand leads to
dimerization and activation by autophosphorylation on tyrosine
residues. In vitro kinase activity is increased by Mg(2+) (By
similarity). {ECO:0000250}.
-!- SUBUNIT: 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, HNRNPU, 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. {ECO:0000250,
ECO:0000269|PubMed:10508857, ECO:0000269|PubMed:16815842}.
-!- INTERACTION:
Q9NZC7:WWOX (xeno); NbExp=3; IntAct=EBI-4398741, EBI-4320739;
-!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:16837552};
Single-pass type I membrane protein {ECO:0000269|PubMed:16837552}.
Note=In response to NRG1 treatment, the activated receptor is
internalized.
-!- SUBCELLULAR LOCATION: ERBB4 intracellular domain: Nucleus.
Mitochondrion {ECO:0000250}. 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). {ECO:0000250}.
-!- ALTERNATIVE PRODUCTS:
Event=Alternative splicing; Named isoforms=3;
Comment=Additional isoforms seem to exist.;
Name=JM-A CYT-1;
IsoId=Q61527-1; Sequence=Displayed;
Note=Proteolytical processing generates E4ICD1 (s80Cyt1).;
Name=JM-B CYT-2;
IsoId=Q61527-2; Sequence=VSP_002896;
Name=JM-A CYT-2;
IsoId=Q61527-3; Sequence=VSP_042131;
Note=Proteolytical processing generates E4ICD2 (s80Cyt2).;
-!- TISSUE SPECIFICITY: 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.
{ECO:0000269|PubMed:10353604}.
-!- PTM: 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). {ECO:0000250}.
-!- PTM: 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).
{ECO:0000250}.
-!- PTM: 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).
{ECO:0000250}.
-!- DISRUPTION PHENOTYPE: 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.
{ECO:0000269|PubMed:10655590, ECO:0000269|PubMed:12824469,
ECO:0000269|PubMed:12954715, ECO:0000269|PubMed:7477376}.
-!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
kinase family. EGF receptor subfamily. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
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EMBL; CU368746; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CU372923; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CU392849; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CU405881; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CU407006; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CU459008; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; CU459207; -; NOT_ANNOTATED_CDS; Genomic_DNA.
EMBL; AK144050; BAE25671.1; -; mRNA.
EMBL; L47241; AAA93534.1; -; mRNA.
EMBL; AF059177; AAC28334.1; -; mRNA.
CCDS; CCDS48285.1; -. [Q61527-3]
RefSeq; NP_034284.1; NM_010154.2. [Q61527-3]
RefSeq; XP_006495755.1; XM_006495692.3. [Q61527-1]
RefSeq; XP_006495756.1; XM_006495693.3. [Q61527-2]
SMR; Q61527; -.
BioGrid; 199498; 5.
DIP; DIP-29887N; -.
IntAct; Q61527; 3.
STRING; 10090.ENSMUSP00000114123; -.
GlyConnect; 2677; -.
iPTMnet; Q61527; -.
PhosphoSitePlus; Q61527; -.
jPOST; Q61527; -.
PaxDb; Q61527; -.
PeptideAtlas; Q61527; -.
PRIDE; Q61527; -.
DNASU; 13869; -.
Ensembl; ENSMUST00000119142; ENSMUSP00000112713; ENSMUSG00000062209. [Q61527-1]
Ensembl; ENSMUST00000121473; ENSMUSP00000114123; ENSMUSG00000062209. [Q61527-3]
GeneID; 13869; -.
KEGG; mmu:13869; -.
UCSC; uc007bjb.1; mouse. [Q61527-3]
CTD; 2066; -.
MGI; MGI:104771; Erbb4.
eggNOG; KOG1025; Eukaryota.
eggNOG; ENOG410XNSR; LUCA.
GeneTree; ENSGT00940000154695; -.
HOGENOM; HOG000230982; -.
InParanoid; Q61527; -.
KO; K05085; -.
OMA; KQNGHIR; -.
OrthoDB; 81952at2759; -.
PhylomeDB; Q61527; -.
TreeFam; TF106002; -.
Reactome; R-MMU-1227986; Signaling by ERBB2.
Reactome; R-MMU-1236394; Signaling by ERBB4.
Reactome; R-MMU-1250196; SHC1 events in ERBB2 signaling.
Reactome; R-MMU-1250342; PI3K events in ERBB4 signaling.
Reactome; R-MMU-1250347; SHC1 events in ERBB4 signaling.
Reactome; R-MMU-1251985; Nuclear signaling by ERBB4.
Reactome; R-MMU-1253288; Downregulation of ERBB4 signaling.
Reactome; R-MMU-1257604; PIP3 activates AKT signaling.
Reactome; R-MMU-1963640; GRB2 events in ERBB2 signaling.
Reactome; R-MMU-1963642; PI3K events in ERBB2 signaling.
Reactome; R-MMU-5673001; RAF/MAP kinase cascade.
Reactome; R-MMU-6785631; ERBB2 Regulates Cell Motility.
Reactome; R-MMU-6811558; PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling.
Reactome; R-MMU-8847993; ERBB2 Activates PTK6 Signaling.
Reactome; R-MMU-8863795; Downregulation of ERBB2 signaling.
Reactome; R-MMU-9018519; Estrogen-dependent gene expression.
ChiTaRS; Erbb4; mouse.
PRO; PR:Q61527; -.
Proteomes; UP000000589; Chromosome 1.
Bgee; ENSMUSG00000062209; Expressed in 238 organ(s), highest expression level in rest of cerebellum marginal layer (mouse).
ExpressionAtlas; Q61527; baseline and differential.
Genevisible; Q61527; MM.
GO; GO:0009925; C:basal plasma membrane; IBA:GO_Central.
GO; GO:0016323; C:basolateral plasma membrane; ISO:MGI.
GO; GO:0005901; C:caveola; ISO:MGI.
GO; GO:0005737; C:cytoplasm; ISO:MGI.
GO; GO:0098982; C:GABA-ergic synapse; IDA:SynGO.
GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO.
GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
GO; GO:0099061; C:integral component of postsynaptic density membrane; IDA:SynGO.
GO; GO:0099056; C:integral component of presynaptic membrane; IDA:SynGO.
GO; GO:0045121; C:membrane raft; ISO:MGI.
GO; GO:0005739; C:mitochondrion; ISO:MGI.
GO; GO:0005634; C:nucleus; ISO:MGI.
GO; GO:0005886; C:plasma membrane; ISO:MGI.
GO; GO:0014069; C:postsynaptic density; ISO:MGI.
GO; GO:0045211; C:postsynaptic membrane; ISS:UniProtKB.
GO; GO:0043235; C:receptor complex; ISO:MGI.
GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
GO; GO:0005154; F:epidermal growth factor receptor binding; ISO:MGI.
GO; GO:0038132; F:neuregulin binding; ISO:MGI.
GO; GO:0042803; F:protein homodimerization activity; ISO:MGI.
GO; GO:0004713; F:protein tyrosine kinase activity; IDA:MGI.
GO; GO:0044212; F:transcription regulatory region DNA binding; ISO:MGI.
GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; ISS:UniProtKB.
GO; GO:0061026; P:cardiac muscle tissue regeneration; IMP:UniProtKB.
GO; GO:0045165; P:cell fate commitment; IDA:MGI.
GO; GO:0016477; P:cell migration; ISS:UniProtKB.
GO; GO:0071364; P:cellular response to epidermal growth factor stimulus; IDA:MGI.
GO; GO:0021551; P:central nervous system morphogenesis; IMP:UniProtKB.
GO; GO:0009880; P:embryonic pattern specification; IMP:UniProtKB.
GO; GO:0007507; P:heart development; IMP:MGI.
GO; GO:0007595; P:lactation; IMP:UniProtKB.
GO; GO:0060749; P:mammary gland alveolus development; IMP:UniProtKB.
GO; GO:0060644; P:mammary gland epithelial cell differentiation; IMP:UniProtKB.
GO; GO:0043653; P:mitochondrial fragmentation involved in apoptotic process; ISS:UniProtKB.
GO; GO:0043066; P:negative regulation of apoptotic process; IDA:MGI.
GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB.
GO; GO:0010656; P:negative regulation of muscle cell apoptotic process; ISO:MGI.
GO; GO:2001223; P:negative regulation of neuron migration; IMP:MGI.
GO; GO:0007399; P:nervous system development; IMP:MGI.
GO; GO:0001755; P:neural crest cell migration; IMP:UniProtKB.
GO; GO:0021889; P:olfactory bulb interneuron differentiation; IMP:UniProtKB.
GO; GO:0038083; P:peptidyl-tyrosine autophosphorylation; IDA:MGI.
GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB.
GO; GO:0043065; P:positive regulation of apoptotic process; IDA:MGI.
GO; GO:0060045; P:positive regulation of cardiac muscle cell proliferation; IMP:UniProtKB.
GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI.
GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:MGI.
GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:MGI.
GO; GO:0070374; P:positive regulation of ERK1 and ERK2 cascade; ISS:UniProtKB.
GO; GO:0046326; P:positive regulation of glucose import; ISO:MGI.
GO; GO:0043552; P:positive regulation of phosphatidylinositol 3-kinase activity; ISS:UniProtKB.
GO; GO:0014068; P:positive regulation of phosphatidylinositol 3-kinase signaling; IGI:MGI.
GO; GO:2000010; P:positive regulation of protein localization to cell surface; IGI:MGI.
GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IMP:UniProtKB.
GO; GO:0032230; P:positive regulation of synaptic transmission, GABAergic; ISO:MGI.
GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:UniProtKB.
GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IMP:UniProtKB.
GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB.
GO; GO:0030334; P:regulation of cell migration; IMP:UniProtKB.
GO; GO:0007165; P:signal transduction; ISO:MGI.
GO; GO:0043129; P:surfactant homeostasis; ISO:MGI.
GO; GO:0007416; P:synapse assembly; IDA:SynGO.
GO; GO:0060074; P:synapse maturation; ISO:MGI.
GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; ISS:UniProtKB.
CDD; cd00064; FU; 3.
Gene3D; 3.80.20.20; -; 2.
InterPro; IPR006211; Furin-like_Cys-rich_dom.
InterPro; IPR006212; Furin_repeat.
InterPro; IPR032778; GF_recep_IV.
InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
InterPro; IPR011009; Kinase-like_dom_sf.
InterPro; IPR000719; Prot_kinase_dom.
InterPro; IPR017441; Protein_kinase_ATP_BS.
InterPro; IPR000494; Rcpt_L-dom.
InterPro; IPR036941; Rcpt_L-dom_sf.
InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
InterPro; IPR008266; Tyr_kinase_AS.
InterPro; IPR020635; Tyr_kinase_cat_dom.
InterPro; IPR016245; Tyr_kinase_EGF/ERB/XmrK_rcpt.
Pfam; PF00757; Furin-like; 1.
Pfam; PF14843; GF_recep_IV; 1.
Pfam; PF07714; Pkinase_Tyr; 1.
Pfam; PF01030; Recep_L_domain; 2.
PIRSF; PIRSF000619; TyrPK_EGF-R; 1.
PRINTS; PR00109; TYRKINASE.
SMART; SM00261; FU; 5.
SMART; SM00219; TyrKc; 1.
SUPFAM; SSF56112; SSF56112; 1.
SUPFAM; SSF57184; SSF57184; 2.
PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
1: Evidence at protein level;
Activator; Alternative splicing; Apoptosis; ATP-binding;
Cell membrane; Complete proteome; Developmental protein;
Disulfide bond; Glycoprotein; Kinase; Lactation; Membrane;
Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; Receptor;
Reference proteome; Repeat; Signal; Transcription;
Transcription regulation; Transferase; Transmembrane;
Transmembrane helix; Tyrosine-protein kinase; Ubl conjugation.
SIGNAL 1 25 {ECO:0000255}.
CHAIN 26 1308 Receptor tyrosine-protein kinase erbB-4.
/FTId=PRO_0000270146.
CHAIN 676 1308 ERBB4 intracellular domain.
/FTId=PRO_0000396798.
TOPO_DOM 26 652 Extracellular. {ECO:0000255}.
TRANSMEM 653 673 {ECO:0000255}.
TOPO_DOM 674 1308 Cytoplasmic. {ECO:0000255}.
DOMAIN 718 985 Protein kinase. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
NP_BIND 724 732 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
NP_BIND 797 799 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
NP_BIND 843 848 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
MOTIF 676 684 Nuclear localization signal.
{ECO:0000250}.
MOTIF 1032 1035 PPxy motif 1. {ECO:0000250}.
MOTIF 1282 1285 PPxY motif 2. {ECO:0000250}.
MOTIF 1290 1292 PDZ-binding. {ECO:0000250}.
COMPBIAS 186 262 Cys-rich.
COMPBIAS 496 593 Cys-rich.
COMPBIAS 1281 1284 Poly-Pro.
ACT_SITE 843 843 Proton acceptor. {ECO:0000255|PROSITE-
ProRule:PRU00159, ECO:0000255|PROSITE-
ProRule:PRU10028}.
BINDING 751 751 ATP. {ECO:0000255|PROSITE-
ProRule:PRU00159}.
MOD_RES 875 875 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1035 1035 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1056 1056 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1150 1150 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1162 1162 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1188 1188 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1202 1202 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1242 1242 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1258 1258 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
MOD_RES 1284 1284 Phosphotyrosine; by autocatalysis.
{ECO:0000250|UniProtKB:Q15303}.
CARBOHYD 138 138 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 174 174 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 181 181 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 253 253 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 410 410 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 473 473 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 495 495 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 548 548 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 576 576 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
CARBOHYD 620 620 N-linked (GlcNAc...) asparagine.
{ECO:0000255}.
DISULFID 29 56 {ECO:0000250}.
DISULFID 156 186 {ECO:0000250}.
DISULFID 189 197 {ECO:0000250}.
DISULFID 193 205 {ECO:0000250}.
DISULFID 213 221 {ECO:0000250}.
DISULFID 217 229 {ECO:0000250}.
DISULFID 230 238 {ECO:0000250}.
DISULFID 234 246 {ECO:0000250}.
DISULFID 249 258 {ECO:0000250}.
DISULFID 262 289 {ECO:0000250}.
DISULFID 293 304 {ECO:0000250}.
DISULFID 308 323 {ECO:0000250}.
DISULFID 326 330 {ECO:0000250}.
DISULFID 503 512 {ECO:0000250}.
DISULFID 507 520 {ECO:0000250}.
DISULFID 523 532 {ECO:0000250}.
DISULFID 536 552 {ECO:0000250}.
DISULFID 555 569 {ECO:0000250}.
DISULFID 559 577 {ECO:0000250}.
DISULFID 580 589 {ECO:0000250}.
DISULFID 593 614 {ECO:0000250}.
DISULFID 617 625 {ECO:0000250}.
DISULFID 621 633 {ECO:0000250}.
VAR_SEQ 626 648 NGPTSHDCIYYPWTGHSTLPQHA -> IGSSIEDCIGLTD
(in isoform JM-B CYT-2).
{ECO:0000303|PubMed:9334263}.
/FTId=VSP_002896.
VAR_SEQ 1046 1061 Missing (in isoform JM-A CYT-2).
{ECO:0000303|PubMed:9334263}.
/FTId=VSP_042131.
CONFLICT 1019 1019 A -> V (in Ref. 5; AAC28334).
{ECO:0000305}.
SEQUENCE 1308 AA; 146855 MW; 65943278A7E7F2F6 CRC64;
MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM
GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF
LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNMTLVST
NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG
PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD
SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT
KINGNLIFLV TGIHGDPYNA IDAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL
VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST
INQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD
GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA
NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG
LFILVIMALT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR
VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL
VRLLGVCLSP TIQLVTQLMP HGCLLDYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV
HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ
SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID
ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE
EYLVPQAFNI PPPIYTSRTR IDSNRSEIGH SPPPAYTPMS GNQFVYQDGG FATQQGMPMP
YRATTSTIPE APVAQGATAE MFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERN
PRGELDEEGY MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED
EYVNEPLYLN TFANALGSAE YMKNSVLSVP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ
EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP YRHRNTVV


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