EKS-MUM-00328

Eukaryotic Protein Kinase & Protein Phosphatase Database

Tag

Content

EKPD ID

EKS-MUM-00328

Classification

Group/Family	Score	E-Value	Start	End	Domain Length
TK/EGFR	502.5	5.4E-151	718	975	258

Status

Reviewed

Ensembl Protein

ENSMUSP00000114123

UniProt Accession

Q61527; B2KGF5; B2KGF6; O88460; Q3UNS6;

Protein Name

ERBB4 intracellular domain

Protein Synonyms/Alias

Proto-oncogene-like protein c-ErbB-4; 4ICD; E4ICD; s80HER4;

Gene Name

Erbb4

Gene Synonyms/Alias

Erbb4; Mer4;

Ensembl Information

Ensembl Gene ID	Ensembl Protein ID	Ensembl Transcript ID
ENSMUSG00000062209	ENSMUSP00000112713	ENSMUST00000119142
ENSMUSG00000062209	ENSMUSP00000115373	ENSMUST00000153432
ENSMUSG00000062209	ENSMUSP00000114123	ENSMUST00000121473

Organism

Mus musculus

Functional Description

Tyrosine-protein kinase that plays an essential role ascell 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 lactaction. The ERBB4 soluble intracellular domains can also translocate to mitochondria and promote apoptosis.

Protein Length

1292

Protein Sequence
(FASTA)

MKLATGLWVW GSLLMAAGTV QPSASQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM 60

GNLEITSIEH NRDLSFLRSI REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF 120

LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNMTLVST 180

NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG 240

PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD 300

SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT 360

KINGNLIFLV TGIHGDPYNA IDAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL 420

VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 480

INQRIVIRDN RRAENCTAEG MVCNHLCSND GCWGPGPDQC LSCRRFSRGK ICIESCNLYD 540

GEFREFENGS ICVECDSQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 600

NSFIFKYADQ DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG 660

LFILVIMALT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR 720

VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL 780

VRLLGVCLSP TIQLVTQLMP HGCLLDYVHE HKDNIGSQLL LNWCVQIAKG MMYLEERRLV 840

HRDLAARNVL VKSPNHVKIT DFGLARLLEG DEKEYNADGG KMPIKWMALE CIHYRKFTHQ 900

SDVWSYGVTI WELMTFGGKP YDGIPTREIP DLLEKGERLP QPPICTIDVY MVMVKCWMID 960

ADSRPKFKEL AAEFSRMARD PQRYLVIQGD DRMKLPSPND SKFFQNLLDE EDLEDMMDAE 1020

EYLVPQAFNI PPPIYTSRTR IDSNRNQFVY QDGGFATQQG MPMPYRATTS TIPEAPVAQG 1080

ATAEMFDDSC CNGTLRKPVA PHVQEDSSTQ RYSADPTVFA PERNPRGELD EEGYMTPMHD 1140

KPKQEYLNPV EENPFVSRRK NGDLQALDNP EYHSASSGPP KAEDEYVNEP LYLNTFANAL 1200

GSAEYMKNSV LSVPEKAKKA FDNPDYWNHS LPPRSTLQHP DYLQEYSTKY FYKQNGRIRP 1260

IVAENPEYLS EFSLKPGTML PPPPYRHRNT VV 1292

Nucleotide Sequence
(FASTA)

ATGAAGCTGG CGACGGGACT CTGGGTCTGG GGGAGCCTTC TGATGGCAGC GGGGACCGTC 60

CAGCCCAGCG CTTCTCAGTC AGTGTGCGCA GGAACAGAGA ACAAACTGAG CTCTCTCTCT 120

GACCTGGAAC AGCAGTACCG AGCCTTGCGC AAATACTATG AAAACTGCGA GGTAGTCATG 180

GGCAACCTGG AGATCACCAG CATCGAGCAC AACCGGGACC TCTCCTTCCT GCGGTCTATC 240

CGAGAAGTCA CAGGCTACGT CCTGGTGGCC CTCAACCAGT TTCGTTACTT GCCTCTGGAG 300

AATTTACGCA TTATTCGTGG GACAAAACTA TATGAAGATC GCTATGCCTT AGCGATATTC 360

TTAAACTACA GGAAAGATGG CAACTTTGGA CTCCAAGAAC TTGGATTAAA GAACCTGACC 420

GAAATACTAA ATGGTGGAGT CTATGTAGAC CAGAACAAAT TCCTATGTTA TGCTGACACT 480

ATACACTGGC AAGATATTGT TCGGAATCCA TGGCCTTCCA ACATGACTCT GGTGTCAACA 540

AATGGAAGTT CTGGATGTGG AAGATGCCAT AAGTCTTGCA CTGGCCGATG CTGGGGACCC 600

ACAGAAAATC ACTGCCAGAC CTTGACCAGA ACTGTGTGTG CTGAACAATG TGATGGCAGG 660

TGCTATGGAC CCTACGTTAG TGACTGCTGC CATCGAGAAT GTGCTGGAGG CTGCTCAGGA 720

CCAAAGGACA CTGACTGCTT TGCCTGCATG AACTTCAATG ACAGTGGAGC CTGCGTTACT 780

CAATGTCCCC AAACATTTGT CTACAATCCA ACCACCTTTC AACTGGAACA CAACTTCAAT 840

GCAAAGTACA CGTATGGAGC ATTCTGTGTT AAGAAATGTC CACATAACTT CGTGGTAGAT 900

TCCAGTTCTT GTGTACGAGC CTGCCCTAGT TCTAAGATGG AAGTAGAAGA AAATGGGATT 960

AAAATGTGTA AGCCTTGCAC CGATATTTGC CCCAAAGCAT GTGATGGAAT CGGCACGGGA 1020

TCACTGATGT CTGCTCAGAC TGTGGATTCA AGTAACATTG ACAAATTCAT AAACTGCACA 1080

AAGATCAATG GCAATCTCAT CTTTCTTGTC ACTGGCATTC ATGGAGACCC TTACAATGCT 1140

ATTGACGCCA TAGATCCAGA GAAACTGAAT GTCTTTCGGA CTGTCAGAGA AATAACAGGT 1200

TTCCTGAACA TACAGTCTTG GCCCCCAAAT ATGACAGATT TCAGTGTTTT CTCCAACCTC 1260

GTCACAATTG GAGGAAGAGT CCTCTACAGT GGTCTCTCAT TGCTGATCCT CAAACAACAA 1320

GGTATCACTT CCCTACAGTT CCAGTCTCTG AAGGAAATCA GTGCGGGCAA TATCTACATC 1380

ACTGACAACA GCAACCTGTG TTATTACCAT ACCATTAACT GGACAACACT CTTCAGCACC 1440

ATTAACCAGA GAATAGTGAT CCGAGATAAC AGAAGAGCTG AGAATTGTAC TGCTGAAGGC 1500

ATGGTATGCA ACCACCTGTG TTCAAATGAT GGTTGTTGGG GACCTGGGCC GGACCAGTGC 1560

CTGTCATGTC GGCGCTTCAG CAGGGGAAAG ATCTGCATAG AGTCTTGCAA CCTTTATGAT 1620

GGGGAATTTC GAGAGTTTGA AAACGGCTCC ATCTGTGTTG AGTGTGACTC CCAGTGTGAG 1680

AAAATGGAAG ATGGACTCCT CACATGCCAT GGACCGGGAC CTGACAACTG CACAAAGTGC 1740

TCTCATTTTA AGGATGGTCC AAACTGTGTG GAGAAATGTC CAGATGGCCT ACAGGGAGCA 1800

AACAGTTTCA TTTTTAAGTA TGCAGATCAG GATCGGGAGT GCCACCCTTG CCATCCAAAC 1860

TGCACCCAGG GGTGTAACGG TCCCACTAGT CATGACTGCA TTTACTACCC ATGGACGGGC 1920

CATTCCACTT TACCACAACA CGCTAGAACT CCACTGATTG CAGCCGGAGT CATTGGAGGC 1980

CTCTTCATCC TGGTGATCAT GGCTTTGACA TTTGCTGTCT ATGTCAGAAG AAAGAGCATC 2040

AAAAAGAAAC GTGCTTTGAG GAGATTCCTG GAGACAGAGC TGGTAGAGCC CTTAACTCCC 2100

AGTGGCACGG CACCCAATCA AGCTCAACTT CGCATTTTGA AGGAAACCGA ACTAAAGAGG 2160

GTAAAGGTCC TTGGCTCGGG AGCTTTTGGA ACCGTTTATA AAGGTATTTG GGTGCCTGAA 2220

GGTGAAACAG TGAAAATCCC TGTGGCTATA AAGATCCTCA ATGAAACAAC TGGCCCCAAA 2280

GCCAACGTGG AGTTCATGGA TGAGGCTCTG ATCATGGCAA GTATGGATCA CCCACACCTA 2340

GTTCGCCTAT TGGGAGTGTG TCTGAGTCCC ACTATCCAGT TGGTTACGCA GCTGATGCCG 2400

CATGGCTGCC TACTGGACTA TGTTCATGAA CACAAGGATA ACATTGGATC ACAGCTGCTG 2460

TTGAACTGGT GTGTCCAGAT TGCTAAGGGA ATGATGTACC TAGAAGAAAG ACGGCTTGTT 2520

CATCGGGATC TGGCAGCCCG CAATGTCTTA GTGAAATCTC CAAATCATGT TAAAATCACA 2580

GATTTTGGAC TGGCCCGGCT CTTGGAAGGA GATGAAAAAG AATACAATGC TGATGGTGGC 2640

AAGATGCCAA TTAAATGGAT GGCTCTGGAA TGTATACATT ATAGGAAATT CACACATCAA 2700

AGTGATGTTT GGAGCTATGG CGTCACTATA TGGGAACTGA TGACCTTTGG AGGAAAGCCC 2760

TATGATGGAA TTCCAACCCG AGAAATCCCC GATTTACTGG AGAAAGGAGA GCGTCTGCCT 2820

CAGCCTCCCA TCTGCACTAT TGATGTTTAC ATGGTCATGG TCAAATGTTG GATGATCGAT 2880

GCTGACAGCA GACCTAAATT CAAAGAACTG GCTGCTGAGT TTTCAAGAAT GGCTAGAGAC 2940

CCTCAAAGAT ACCTAGTTAT TCAGGGTGAT GATCGTATGA AGCTTCCCAG TCCAAATGAC 3000

AGCAAATTCT TCCAGAATCT CTTGGATGAA GAGGATTTGG AAGACATGAT GGATGCTGAG 3060

GAATATTTGG TCCCCCAGGC TTTCAACATA CCTCCTCCCA TCTACACATC CAGAACAAGA 3120

ATTGACTCCA ATAGGAATCA GTTTGTGTAC CAAGATGGGG GCTTTGCTAC ACAACAAGGA 3180

ATGCCCATGC CCTACAGAGC CACAACCAGC ACCATACCAG AGGCTCCAGT AGCTCAGGGT 3240

GCAACGGCTG AGATGTTTGA TGACTCCTGC TGTAATGGTA CCCTACGAAA GCCAGTGGCA 3300

CCCCATGTCC AAGAGGACAG TAGCACTCAG AGGTATAGTG CTGATCCCAC AGTGTTCGCC 3360

CCAGAACGGA ATCCTCGAGG AGAACTGGAT GAAGAAGGCT ACATGACTCC AATGCATGAC 3420

AAGCCCAAAC AAGAATATCT GAATCCTGTG GAAGAGAACC CTTTTGTGTC CCGAAGGAAG 3480

AATGGAGATC TTCAAGCTTT AGATAATCCG GAGTATCACA GTGCTTCCAG CGGTCCACCC 3540

AAGGCGGAGG ATGAATACGT GAATGAGCCT CTATACCTCA ACACCTTCGC CAATGCCTTG 3600

GGGAGTGCAG AGTACATGAA AAACAGTGTA CTGTCTGTGC CAGAGAAAGC CAAGAAAGCA 3660

TTTGACAACC CCGACTACTG GAACCACAGC CTGCCACCCC GGAGCACCCT TCAGCACCCA 3720

GACTACCTGC AGGAATACAG CACAAAATAT TTTTATAAAC AGAATGGACG GATCCGCCCC 3780

ATTGTGGCAG AGAATCCTGA GTACCTCTCG GAGTTCTCGC TGAAGCCTGG CACTATGCTG 3840

CCCCCTCCGC CCTACAGACA CCGGAATACT GTGGTGTGA 3879

Domain Profile

S: 1     lkklkvlGsGafGtvykGiwipegenvkipvaikvleektgkkankelldealvlasldh  60

         lk++kvlGsGafGtvykGiw+pege+vkipvaik+l+e+tg+kan e++deal++as+dh

Q: 718   LKRVKVLGSGAFGTVYKGIWVPEGETVKIPVAIKILNETTGPKANVEFMDEALIMASMDH  777

         699*********************************************************

S: 61    anlvrllglclsstlqlvtqllplGclldyvrehkdklGsqellnwcvqiakGmsyleek  120

         ++lvrllg+cls t+qlvtql+p+Gclldyv+ehkd++Gsq llnwcvqiakGm+ylee+

Q: 778   PHLVRLLGVCLSPTIQLVTQLMPHGCLLDYVHEHKDNIGSQLLLNWCVQIAKGMMYLEER  837

         ************************************************************

S: 121   rlvhrdlaarnvlvkspnhvkitdfGlaklleadekelkaeggkvpikwlalesilkrky  180

         rlvhrdlaarnvlvkspnhvkitdfGla+lle deke++a+ggk+pikw+ale+i++rk+

Q: 838   RLVHRDLAARNVLVKSPNHVKITDFGLARLLEGDEKEYNADGGKMPIKWMALECIHYRKF  897

         ************************************************************

S: 181   thqsdvwsyGvtvwelltfGakpydgipakeipdllekGerlaqppictidvymvlvkcw  240

         thqsdvwsyGvt+wel+tfG kpydgip++eipdllekGerl+qppictidvymv+vkcw

Q: 898   THQSDVWSYGVTIWELMTFGGKPYDGIPTREIPDLLEKGERLPQPPICTIDVYMVMVKCW  957

         ************************************************************

S: 241   midaesrpkfkelaeefs  258

         mida+srpkfkela+efs

Q: 958   MIDADSRPKFKELAAEFS  975

         ****************96

Domain Sequence
(FASTA)

LKRVKVLGSG AFGTVYKGIW VPEGETVKIP VAIKILNETT GPKANVEFMD EALIMASMDH 60

PHLVRLLGVC LSPTIQLVTQ LMPHGCLLDY VHEHKDNIGS QLLLNWCVQI AKGMMYLEER 120

RLVHRDLAAR NVLVKSPNHV KITDFGLARL LEGDEKEYNA DGGKMPIKWM ALECIHYRKF 180

THQSDVWSYG VTIWELMTFG GKPYDGIPTR EIPDLLEKGE RLPQPPICTI DVYMVMVKCW 240

MIDADSRPKF KELAAEFS 258

Keyword

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; Tumor suppressor; Tyrosine-protein kinase; Ubl conjugation.

Sequence Source

Ensembl

Orthology

Ortholog group

Ailuropoda melanoleuca"; ?>Anolis carolinensis"; ?>Bos taurus"; ?>Caenorhabditis elegans"; ?>Callithrix jacchus"; ?>Canis familiaris"; ?>Cavia porcellus"; ?>Ciona intestinalis"; ?>Equus caballus"; ?>Gallus gallus"; ?>Gasterosteus aculeatus"; ?>Gorilla gorilla"; ?>Homo sapiens"; ?>Latimeria chalumnae"; ?>Loxodonta africana"; ?>Macaca mulatta"; ?>Meleagris gallopavo"; ?>Monodelphis domestica"; ?>Mustela putorius furo"; ?>Myotis lucifugus"; ?>Nomascus leucogenys"; ?>Oreochromis niloticus"; ?>Ornithorhynchus anatinus"; ?>Oryctolagus cuniculus"; ?>Oryzias latipes"; ?>Otolemur garnettii"; ?>Pan troglodytes"; ?>Pelodiscus sinensis"; ?>Petromyzon marinus"; ?>Pongo abelii"; ?>Rattus norvegicus"; ?>Sus scrofa"; ?>Taeniopygia guttata"; ?>Takifugu rubripes"; ?>Tetraodon nigroviridis"; ?>Vicugna pacos"; ?>Xenopus tropicalis"; ?>Xiphophorus maculatus"; ?>

Gene Ontology

GO:0016323	; C:basolateral plasma membrane
GO:0005901	; C:caveola
GO:0016021	; C:integral to membrane
GO:0005739	; C:mitochondrion
GO:0005634	; C:nucleus
GO:0014069	; C:postsynaptic density
GO:0005524	; F:ATP binding
GO:0004716	; F:receptor signaling protein tyrosine kinase activity
GO:0044212	; F:transcription regulatory region DNA binding
GO:0004714	; F:transmembrane receptor protein tyrosine kinase activity
GO:0006915	; P:apoptotic process
GO:0061026	; P:cardiac muscle tissue regeneration
GO:0045165	; P:cell fate commitment
GO:0021551	; P:central nervous system morphogenesis
GO:0009880	; P:embryonic pattern specification
GO:0007507	; P:heart development
GO:0007595	; P:lactation
GO:0060749	; P:mammary gland alveolus development
GO:0060644	; P:mammary gland epithelial cell differentiation
GO:0043066	; P:negative regulation of apoptotic process
GO:0008285	; P:negative regulation of cell proliferation
GO:0001755	; P:neural crest cell migration
GO:0021889	; P:olfactory bulb interneuron differentiation
GO:0018108	; P:peptidyl-tyrosine phosphorylation
GO:0060045	; P:positive regulation of cardiac muscle cell proliferation
GO:0030335	; P:positive regulation of cell migration
GO:0050679	; P:positive regulation of epithelial cell proliferation
GO:0070374	; P:positive regulation of ERK1 and ERK2 cascade
GO:0046326	; P:positive regulation of glucose import
GO:0043552	; P:positive regulation of phosphatidylinositol 3-kinase activity
GO:2000366	; P:positive regulation of STAT protein import into nucleus
GO:0032230	; P:positive regulation of synaptic transmission, GABAergic
GO:0045893	; P:positive regulation of transcription, DNA-dependent
GO:0042523	; P:positive regulation of tyrosine phosphorylation of Stat5 protein
GO:0046777	; P:protein autophosphorylation
GO:0030334	; P:regulation of cell migration
GO:0042493	; P:response to drug
GO:0042542	; P:response to hydrogen peroxide
GO:0032570	; P:response to progesterone stimulus
GO:0023014	; P:signal transduction by phosphorylation
GO:0043129	; P:surfactant homeostasis
GO:0060074	; P:synapse maturation
GO:0006351	; P:transcription, DNA-dependent
GO:0007169	; P:transmembrane receptor protein tyrosine kinase signaling pathway

KEGG

mmu:13869

;

InterPros

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.

Pfam

PF00757	; Furin-like; 1.
PF07714	; Pkinase_Tyr; 1.
PF01030	; Recep_L_domain; 2.

SMARTs

SM00261	; FU; 5.
SM00219	; TyrKc; 1.

Prosites

PS00107	; PROTEIN_KINASE_ATP; 1.
PS50011	; PROTEIN_KINASE_DOM; 1.
PS00109	; PROTEIN_KINASE_TYR; 1.

Prints

PR00109

; TYRKINASE.

Created Date

20-Feb-2013