Q61527 (ERBB4_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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:

1. ERBB4 intracellular domain
   Short name=4ICD
   Short name=E4ICD
   Alternative name(s):
   s80HER4

Gene names

Name:	Erbb4
Synonyms:	Mer4

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1308 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

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. Ref.6 Ref.7 Ref.9 Ref.12 Ref.13 Ref.15 Ref.16 Ref.17
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Enzyme regulation	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.
Subunit structure	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. Ref.7 Ref.14
Subcellular location	Cell membrane; Single-pass type I membrane protein. Note: In response to NRG1 treatment, the activated receptor is internalized. Ref.15 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. Ref.15
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. Ref.8
Post-translational modification	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. 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. 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.
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. Ref.6 Ref.9 Ref.10 Ref.11
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Apoptosis Lactation Transcription Transcription regulation
Cellular component	Cell membrane Membrane Mitochondrion Nucleus
Coding sequence diversity	Alternative splicing
Disease	Tumor suppressor
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Activator Developmental protein Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB cardiac muscle tissue regeneration Inferred from mutant phenotype Ref.17. Source: UniProtKB cell fate commitment Inferred from direct assay PubMed 12399441. Source: MGI central nervous system morphogenesis Inferred from mutant phenotype Ref.9. Source: UniProtKB embryonic pattern specification Inferred from mutant phenotype Ref.9. Source: UniProtKB heart development Inferred from mutant phenotype Ref.6. Source: MGI lactation Inferred from mutant phenotype Ref.7. Source: UniProtKB mammary gland alveolus development Inferred from mutant phenotype Ref.7. Source: UniProtKB mammary gland epithelial cell differentiation Inferred from mutant phenotype Ref.15. Source: UniProtKB negative regulation of apoptotic process Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of cell proliferation Inferred from sequence or structural similarity. Source: UniProtKB neural crest cell migration Inferred from mutant phenotype Ref.9. Source: UniProtKB olfactory bulb interneuron differentiation Inferred from mutant phenotype Ref.12. Source: UniProtKB peptidyl-tyrosine phosphorylation Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of ERK1 and ERK2 cascade Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of STAT protein import into nucleus Inferred from mutant phenotype Ref.15. Source: UniProtKB positive regulation of cardiac muscle cell proliferation Inferred from mutant phenotype Ref.17. Source: UniProtKB positive regulation of phosphatidylinositol 3-kinase activity Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of transcription, DNA-dependent Inferred from mutant phenotype Ref.15. Source: UniProtKB positive regulation of tyrosine phosphorylation of Stat5 protein Inferred from mutant phenotype Ref.7Ref.15. Source: UniProtKB protein autophosphorylation Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell migration Inferred from mutant phenotype Ref.12. Source: UniProtKB signal transduction by phosphorylation Inferred from electronic annotation. Source: GOC transcription, DNA-dependent Inferred from electronic annotation. Source: UniProtKB-KW transmembrane receptor protein tyrosine kinase signaling pathway Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	basolateral plasma membrane Inferred from electronic annotation. Source: Compara integral to membrane Inferred from electronic annotation. Source: UniProtKB-KW mitochondrion Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW receptor signaling protein tyrosine kinase activity Inferred from electronic annotation. Source: InterPro transcription regulatory region DNA binding Inferred from electronic annotation. Source: Compara transmembrane receptor protein tyrosine kinase activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
WWOX	Q9NZC7	3	EBI-4398741,EBI-4320739	From a different organism.

Alternative products

This entry describes 3 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

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

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.

Note: Proteolytical processing generates E4ICD1 (s80Cyt1).

Isoform JM-B CYT-2 (identifier: Q61527-2)

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

Isoform JM-A CYT-2 (identifier: Q61527-3)

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

Note: Proteolytical processing generates E4ICD2 (s80Cyt2).

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 25	25	Potential
	Chain	26 – 1308	1283	Receptor tyrosine-protein kinase erbB-4		PRO_0000270146
	Chain	676 – 1308	633	ERBB4 intracellular domain		PRO_0000396798
Regions
	Topological domain	26 – 652	627	Extracellular Potential
	Transmembrane	653 – 673	21	Potential
	Topological domain	674 – 1308	635	Cytoplasmic Potential
	Domain	718 – 985	268	Protein kinase
	Nucleotide binding	724 – 732	9	ATP By similarity
	Nucleotide binding	797 – 799	3	ATP By similarity
	Nucleotide binding	843 – 848	6	ATP By similarity
	Motif	676 – 684	9	Nuclear localization signal By similarity
	Motif	1032 – 1035	4	PPxy motif 1 By similarity
	Motif	1282 – 1285	4	PPxY motif 2 By similarity
	Motif	1290 – 1292	3	PDZ-binding By similarity
	Compositional bias	186 – 262	77	Cys-rich
	Compositional bias	496 – 593	98	Cys-rich
	Compositional bias	1281 – 1284	4	Poly-Pro
Sites
	Active site	843	1	Proton acceptor By similarity
	Binding site	751	1	ATP By similarity
Amino acid modifications
	Modified residue	875	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1035	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1056	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1150	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1162	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1188	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1202	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1242	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1258	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1284	1	Phosphotyrosine; by autocatalysis By similarity
	Glycosylation	138	1	N-linked (GlcNAc...) Potential
	Glycosylation	174	1	N-linked (GlcNAc...) Potential
	Glycosylation	181	1	N-linked (GlcNAc...) Potential
	Glycosylation	253	1	N-linked (GlcNAc...) Potential
	Glycosylation	410	1	N-linked (GlcNAc...) Potential
	Glycosylation	473	1	N-linked (GlcNAc...) Potential
	Glycosylation	495	1	N-linked (GlcNAc...) Potential
	Glycosylation	548	1	N-linked (GlcNAc...) Potential
	Glycosylation	576	1	N-linked (GlcNAc...) Potential
	Glycosylation	620	1	N-linked (GlcNAc...) Potential
	Disulfide bond	29 ↔ 56		By similarity
	Disulfide bond	156 ↔ 186		By similarity
	Disulfide bond	189 ↔ 197		By similarity
	Disulfide bond	193 ↔ 205		By similarity
	Disulfide bond	213 ↔ 221		By similarity
	Disulfide bond	217 ↔ 229		By similarity
	Disulfide bond	230 ↔ 238		By similarity
	Disulfide bond	234 ↔ 246		By similarity
	Disulfide bond	249 ↔ 258		By similarity
	Disulfide bond	262 ↔ 289		By similarity
	Disulfide bond	293 ↔ 304		By similarity
	Disulfide bond	308 ↔ 323		By similarity
	Disulfide bond	326 ↔ 330		By similarity
	Disulfide bond	503 ↔ 512		By similarity
	Disulfide bond	507 ↔ 520		By similarity
	Disulfide bond	523 ↔ 532		By similarity
	Disulfide bond	536 ↔ 552		By similarity
	Disulfide bond	555 ↔ 569		By similarity
	Disulfide bond	559 ↔ 577		By similarity
	Disulfide bond	580 ↔ 589		By similarity
	Disulfide bond	593 ↔ 614		By similarity
	Disulfide bond	617 ↔ 625		By similarity
	Disulfide bond	621 ↔ 633		By similarity
Natural variations
	Alternative sequence	626 – 648	23	NGPTS…LPQHA → IGSSIEDCIGLTD in isoform JM-B CYT-2.		VSP_002896
	Alternative sequence	1046 – 1061	16	Missing in isoform JM-A CYT-2.		VSP_042131
Experimental info
	Sequence conflict	1019	1	A → V in AAC28334. Ref.5

Sequences

	Sequence		Length	Mass (Da)
	Isoform JM-A CYT-1 [UniParc]. Last modified January 25, 2012. Version 5. Checksum: 65943278A7E7F2F6	FASTA	1,308	146,855
	10 20 30 40 50 60 MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM 70 80 90 100 110 120 GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF 130 140 150 160 170 180 LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNMTLVST 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 IDAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL 430 440 450 460 470 480 VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 490 500 510 520 530 540 INQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD 550 560 570 580 590 600 GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 610 620 630 640 650 660 NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG 670 680 690 700 710 720 LFILVIMALT 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 HGCLLDYVHE 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 PPPIYTSRTR IDSNRSEIGH SPPPAYTPMS GNQFVYQDGG FATQQGMPMP 1090 1100 1110 1120 1130 1140 YRATTSTIPE APVAQGATAE MFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERN 1150 1160 1170 1180 1190 1200 PRGELDEEGY MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED 1210 1220 1230 1240 1250 1260 EYVNEPLYLN TFANALGSAE YMKNSVLSVP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ 1270 1280 1290 1300 EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP YRHRNTVV
	Isoform JM-B CYT-2 [UniParc]. Checksum: 22EF9A9BE932C0F7	FASTA	1,298	145,595
	10 20 30 40 50 60 MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM 70 80 90 100 110 120 GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF 130 140 150 160 170 180 LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNMTLVST 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 IDAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL 430 440 450 460 470 480 VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 490 500 510 520 530 540 INQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD 550 560 570 580 590 600 GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 610 620 630 640 650 660 NSFIFKYADQ DRECHPCHPN CTQGCIGSSI EDCIGLTDRT PLIAAGVIGG LFILVIMALT 670 680 690 700 710 720 FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR VKVLGSGAFG 730 740 750 760 770 780 TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL VRLLGVCLSP 790 800 810 820 830 840 TIQLVTQLMP HGCLLDYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV HRDLAARNVL 850 860 870 880 890 900 VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ SDVWSYGVTI 910 920 930 940 950 960 WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID ADSRPKFKEL 970 980 990 1000 1010 1020 AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE EYLVPQAFNI 1030 1040 1050 1060 1070 1080 PPPIYTSRTR IDSNRSEIGH SPPPAYTPMS GNQFVYQDGG FATQQGMPMP YRATTSTIPE 1090 1100 1110 1120 1130 1140 APVAQGATAE MFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERN PRGELDEEGY 1150 1160 1170 1180 1190 1200 MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED EYVNEPLYLN 1210 1220 1230 1240 1250 1260 TFANALGSAE YMKNSVLSVP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ EYSTKYFYKQ 1270 1280 1290 NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP YRHRNTVV
	Isoform JM-A CYT-2 [UniParc]. Checksum: 46FBDC6AE4D69E08	FASTA	1,292	145,245
	10 20 30 40 50 60 MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM 70 80 90 100 110 120 GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF 130 140 150 160 170 180 LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNMTLVST 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 IDAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL 430 440 450 460 470 480 VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 490 500 510 520 530 540 INQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD 550 560 570 580 590 600 GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 610 620 630 640 650 660 NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG 670 680 690 700 710 720 LFILVIMALT 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 HGCLLDYVHE 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 PPPIYTSRTR IDSNRNQFVY QDGGFATQQG MPMPYRATTS TIPEAPVAQG 1090 1100 1110 1120 1130 1140 ATAEMFDDSC CNGTLRKPVA PHVQEDSSTQ RYSADPTVFA PERNPRGELD EEGYMTPMHD 1150 1160 1170 1180 1190 1200 KPKQEYLNPV EENPFVSRRK NGDLQALDNP EYHSASSGPP KAEDEYVNEP LYLNTFANAL 1210 1220 1230 1240 1250 1260 GSAEYMKNSV LSVPEKAKKA FDNPDYWNHS LPPRSTLQHP DYLQEYSTKY FYKQNGRIRP 1270 1280 1290 IVAENPEYLS EFSLKPGTML PPPPYRHRNT VV

References

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[1]	"Lineage-specific biology revealed by a finished genome assembly of the mouse." 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. PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract] 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 IN ACTIVATION OF STAT5A TRANSCRIPTION ACTIVATION.
[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.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	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.
IPI	IPI00122341. IPI00357770. IPI00896073. IPI01023082.
RefSeq	NP_034284.1. NM_010154.1.
UniGene	Mm.442420.
3D structure databases
ProteinModelPortal	Q61527.
SMR	Q61527. Positions 26-639, 642-1026.
ModBase	Search...
Protein-protein interaction databases
DIP	DIP-29887N.
IntAct	Q61527. 2 interactions.
STRING	10090.ENSMUSP00000112713.
Proteomic databases
PaxDb	Q61527.
PRIDE	Q61527.
Protocols and materials databases
DNASU	13869.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000119142; ENSMUSP00000112713; ENSMUSG00000062209. ENSMUST00000121473; ENSMUSP00000114123; ENSMUSG00000062209.
GeneID	13869.
KEGG	mmu:13869.
Organism-specific databases
CTD	2066.
MGI	MGI:104771. Erbb4.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00600000084253.
HOGENOM	HOG000230982.
HOVERGEN	HBG000490.
InParanoid	B2KGF6.
KO	K05085.
OMA	CNGPTSH.
OrthoDB	EOG4T4CTM.
Gene expression databases
ArrayExpress	Q61527.
Bgee	Q61527.
Genevestigator	Q61527.
GermOnline	ENSMUSG00000062209. Mus musculus.
Family and domain databases
InterPro	IPR000494. EGF_rcpt_L. IPR006211. Furin-like_Cys-rich_dom. IPR006212. Furin_repeat. IPR009030. Growth_fac_rcpt. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_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]
Pfam	PF00757. Furin-like. 1 hit. PF07714. Pkinase_Tyr. 1 hit. PF01030. Recep_L_domain. 2 hits. [Graphical view]
PIRSF	PIRSF000619. TyrPK_EGF-R. 1 hit.
PRINTS	PR00109. TYRKINASE.
SMART	SM00261. FU. 5 hits. SM00219. TyrKc. 1 hit. [Graphical view]
SUPFAM	SSF57184. Grow_fac_recept. 2 hits. SSF56112. Kinase_like. 1 hit.
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	284772.
SOURCE	Search...

Entry information

Entry name

ERBB4_MOUSE

Accession

Primary (citable) accession number: Q61527
Secondary accession number(s): B2KGF5 , B2KGF6, O88460, Q3UNS6

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 15, 1998
Last sequence update:	January 25, 2012
Last modified:	April 3, 2013
This is version 120 of the entry and version 5 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program