Reviewed, UniProtKB/Swiss-Prot Q62956 (ERBB4_RAT)

Names and origin

Protein names

Recommended name:
    Receptor tyrosine-protein kinase erbB-4
    EC=2.7.10.1
Alternative name(s):
    c-erbB-4

Gene names

Name:	Erbb4
Synonyms:	Tyro-2

Organism

Rattus norvegicus (Rat)

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

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 transcript level.

General annotation (Comments)

Function	Specifically binds and is activated by neuregulins, NRG-2, NRG-3, heparin-binding EGF-like growth factor, betacellulin and NTAK. Interaction with these factors induces cell differentiation. Not activated by EGF, TGF-A, and amphiregulin By similarity.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	Homodimer or heterodimer with each of the other ERBB receptors. Interacts with PDZ domains of DLG2, DLG3, DLG4 and the syntrophin SNTB2. Interacts with CBFA2T3, MUC1 and WWOX By similarity.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Preferentially expressed in the developing nervous system. Exhibits distinct and highly regionalized patterns of expression in the adult brain, where it is mainly found in the reticular nucleus of the thallamus. Very low levels in kidney, and heart.
Domain	The WW-binding motifs mediate interaction with WWOX By similarity.
Post-translational modification	Ligand-binding increases phosphorylation on tyrosine residues By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. EGF receptor subfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Alternative splicing
Domain	Repeat Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Gene Ontology (GO)
Biological process	mammary gland development Inferred from expression pattern. Source: RGD odontogenesis Inferred from expression pattern. Source: RGD peptidyl-tyrosine phosphorylation Inferred from electronic annotation. Source: InterPro positive regulation of anti-apoptosis Inferred from mutant phenotype. Source: RGD positive regulation of cell migration Ref.2 Inferred from mutant phenotype. Source: RGD positive regulation of epithelial cell proliferation Inferred from mutant phenotype. Source: RGD positive regulation of glucose import Inferred from mutant phenotype. Source: RGD positive regulation of synaptic transmission, GABAergic Inferred from mutant phenotype. Source: RGD response to drug Inferred from expression pattern. Source: RGD response to hydrogen peroxide Inferred from expression pattern. Source: RGD response to progesterone stimulus Inferred from expression pattern. Source: RGD surfactant homeostasis Inferred from mutant phenotype. Source: RGD synapse maturation Inferred from mutant phenotype. Source: RGD telencephalon development Inferred from expression pattern. Source: RGD transmembrane receptor protein tyrosine kinase signaling pathway Traceable author statement. Source: RGD
Cellular component	caveola Inferred from direct assay. Source: RGD cytoplasm Inferred from direct assay. Source: RGD integral to membrane Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay. Source: RGD postsynaptic density Inferred from direct assay. Source: RGD
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from direct assay. Source: RGD receptor signaling protein tyrosine kinase activity Inferred from electronic annotation. Source: InterPro transmembrane receptor protein tyrosine kinase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q62956-1)

Also known as: JMa cyt1;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q62956-2)

Also known as: JMa cyt2;

The sequence of this isoform differs from the canonical sequence as follows:
     1046-1062: SEIGHSPPPAYTPMSGS → N

Note: No experimental confirmation available.

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_0000016675
Regions
	Topological domain	26 – 651	626	Extracellular Potential
	Transmembrane	652 – 675	24	Potential
	Topological domain	676 – 1308	633	Cytoplasmic Potential
	Domain	718 – 985	268	Protein kinase
	Nucleotide binding	724 – 732	9	ATP By similarity
	Motif	1032 – 1035	4	WW-binding 1
	Motif	1298 – 1301	4	WW-binding 2
	Motif	1306 – 1308	3	PDZ-binding
	Compositional bias	186 – 334	149	Cys-rich
	Compositional bias	496 – 633	138	Cys-rich
Sites
	Active site	843	1	Proton acceptor By similarity
	Binding site	751	1	ATP By similarity
Amino acid modifications
	Modified residue	733	1	Phosphotyrosine By similarity
	Modified residue	1162	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	1188	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	253	1	N-linked (GlcNAc...) Potential
	Glycosylation	358	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	1046 – 1062	17	SEIGH…PMSGS → N in isoform 2.		VSP_022150
Experimental info
	Sequence conflict	406	1	T → S in AAQ77348. Ref.2
	Sequence conflict	406	1	T → S in AAQ77349. Ref.2
	Sequence conflict	596	1	V → G in AAQ77348. Ref.2
	Sequence conflict	596	1	V → G in AAQ77349. Ref.2
	Sequence conflict	951	1	I → M in AAQ77348. Ref.2
	Sequence conflict	951	1	I → M in AAQ77349. Ref.2
	Sequence conflict	1062	1	S → N in AAQ77348. Ref.2
	Sequence conflict	1062	1	S → N in AAC53051. Ref.4
	Sequence conflict	1080 – 1082	3	PYT → SYR in AAC53051. Ref.4
	Sequence conflict	1082	1	T → R in AAQ77348. Ref.2
	Sequence conflict	1082	1	T → R in AAQ77349. Ref.2

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 (JMa cyt1) [UniParc]. Last modified June 6, 2002. Version 3. Checksum: D944BB0996A08B41	FASTA	1,308	146,958
	10 20 30 40 50 60 MKLATGLWVW GSLLVAARTV 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 IGSSGCGRCH 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 FLNIQTWPPN MTDFSVFSNL 430 440 450 460 470 480 VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 490 500 510 520 530 540 VNQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD 550 560 570 580 590 600 GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDVLQGA 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 IMASVDHPHL 790 800 810 820 830 840 VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV 850 860 870 880 890 900 HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ 910 920 930 940 950 960 SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY IVMVKCWMID 970 980 990 1000 1010 1020 ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE 1030 1040 1050 1060 1070 1080 EYLVPQAFNI PPPIYTSRTR IDSNRSEIGH SPPPAYTPMS GSQFVYQDGG FATQQGMPMP 1090 1100 1110 1120 1130 1140 YTATTSTIPE APVAQGATAE MFDDSCCNGT LRKPVVPHVQ EDSSTQRYSA DPTVFAPERN 1150 1160 1170 1180 1190 1200 PRAELDEEGY MTPMHDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHS ASSGPPKAED 1210 1220 1230 1240 1250 1260 EYVNEPLYLN TFTNALGNAE YMKNSLLSVP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ 1270 1280 1290 1300 EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTMLPPPP YRHRNTVV
	Isoform 2 (JMa cyt2). Checksum: 4249D5FD4B5A9272	FASTA	1,292	145,376
	10 20 30 40 50 60 MKLATGLWVW GSLLVAARTV 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 IGSSGCGRCH 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 FLNIQTWPPN MTDFSVFSNL 430 440 450 460 470 480 VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 490 500 510 520 530 540 VNQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD 550 560 570 580 590 600 GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDVLQGA 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 IMASVDHPHL 790 800 810 820 830 840 VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV 850 860 870 880 890 900 HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ 910 920 930 940 950 960 SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY IVMVKCWMID 970 980 990 1000 1010 1020 ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE 1030 1040 1050 1060 1070 1080 EYLVPQAFNI PPPIYTSRTR IDSNRNQFVY QDGGFATQQG MPMPYTATTS TIPEAPVAQG 1090 1100 1110 1120 1130 1140 ATAEMFDDSC CNGTLRKPVV PHVQEDSSTQ RYSADPTVFA PERNPRAELD EEGYMTPMHD 1150 1160 1170 1180 1190 1200 KPKQEYLNPV EENPFVSRRK NGDLQALDNP EYHSASSGPP KAEDEYVNEP LYLNTFTNAL 1210 1220 1230 1240 1250 1260 GNAEYMKNSL LSVPEKAKKA FDNPDYWNHS LPPRSTLQHP DYLQEYSTKY FYKQNGRIRP 1270 1280 1290 IVAENPEYLS EFSLKPGTML PPPPYRHRNT VV

References

[1]	"Neuregulins promote survival and growth of cardiac myocytes. Persistence of ErbB2 and ErbB4 expression in neonatal and adult ventricular myocytes." Zhao Y.-Y., Sawyer D.R., Baliga R.R., Opel D.J., Han X., Marchionni M.A., Kelly R.A. J. Biol. Chem. 273:10261-10269(1998) [PubMed: 9553078] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). Tissue: Heart.
[2]	"ErbB4 expression in neural progenitor cells (ST14A) is necessary to mediate neuregulin-1-beta1-induced migration." Gambarotta G., Garzotto D., Destro E., Mautino B., Giampietro C., Cutrupi S., Dati C., Cattaneo E., Fasolo A., Perroteau I. J. Biol. Chem. 279:48808-48816(2004) [PubMed: 15355992] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2). Strain: Wistar. Tissue: Olfactory bulb.
[3]	"An extended family of protein-tyrosine kinase genes differentially expressed in the vertebrate nervous system." Lai C., Lemke G. Neuron 6:691-704(1991) [PubMed: 2025425] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 848-901. Tissue: Sciatic nerve.
[4]	"Expression of neuregulins and their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration." Carroll S.L., Miller M.L., Frohnert P.W., Kim S.S., Corbett J.A. J. Neurosci. 17:1642-1659(1997) [PubMed: 9030624] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 1031-1198. Strain: Sprague-Dawley. Tissue: Spinal cord.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AF041838 mRNA. Translation: AAD08899.1. AY375306 mRNA. Translation: AAQ77348.1. AY375307 mRNA. Translation: AAQ77349.1. U52531 mRNA. Translation: AAC53051.1.
IPI	IPI00210292. IPI00778194.
PIR	PT0184.
RefSeq	NP_067719.1.
UniGene	Rn.163078
3D structure databases
SMR	Q62956. Positions 26-639, 694-991, 702-1025.
ModBase	Search...
Protein-protein interaction databases
STRING	Q62956.
PTM databases
PhosphoSite	Q62956.
Genome annotation databases
Ensembl	ENSRNOT00000019283; ENSRNOP00000019283; ENSRNOG00000014248; Rattus norvegicus. [Genome view]
GeneID	59323.
KEGG	rno:59323.
UCSC	NM_021687. rat.
Organism-specific databases
CTD	59323.
RGD	620486. Erbb4.
Phylogenomic databases
eggNOG	roNOG05099.
HOVERGEN	Q62956.
InParanoid	Q62956.
Enzyme and pathway databases
BRENDA	2.7.10.1. 248.
Gene expression databases
ArrayExpress	Q62956.
Genevestigator	Q62956.
GermOnline	ENSRNOG00000014248. Rattus norvegicus.
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. IPR016245. Tyr_kinase_EGF/ERB/XmrK_rcpt. IPR020635. Tyr_Pkinase_cat_dom. IPR020685. Tyr_prot_kinase. IPR008266. Tyr_prot_kinase_AS. IPR020690. Tyr_prot_kinase_rcpt_erbB4. [Graphical view]
PANTHER	PTHR23256. Tyr_prot_kinase. 1 hit. PTHR23256:SF24. Tyr_prot_kinase_rcpt_erbB4. 1 hit.
Pfam	PF00757. Furin-like. 1 hit. PF01030. Recep_L_domain. 2 hits. [Graphical view]
PIRSF	PIRSF000619. TyrPK_EGF-R. 1 hit.
SMART	SM00261. FU. 5 hits. SM00219. TyrKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00109. PROTEIN_KINASE_TYR. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	611909.

Entry information

Entry name

ERBB4_RAT

Accession

Primary (citable) accession number: Q62956
Secondary accession number(s): Q6UA28, Q6UA29, Q9Z2N7

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 15, 1998
Last sequence update:	June 6, 2002
Last modified:	February 9, 2010
This is version 103 of the entry and version 3 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)