EKS-HOS-00303

Eukaryotic Protein Kinase & Protein Phosphatase Database

Tag

Content

EKPD ID

EKS-HOS-00303

Classification

Group/Family	Score	E-Value	Start	End	Domain Length
TK/EGFR	501.3	2.6E-150	718	975	258

Status

Reviewed

Ensembl Protein

ENSP00000342235

UniProt Accession

Q15303; B7ZLD7; B7ZLE2; B7ZLE3; Q2M1W1; Q59EW4;

Protein Name

ERBB4 intracellular domain

Protein Synonyms/Alias

Proto-oncogene-like protein c-ErbB-4; Tyrosine kinase-type cell surface receptor HER4; p180erbB4; 4ICD; E4ICD; s80HER4;

Gene Name

ERBB4

Gene Synonyms/Alias

ERBB4; HER4;

Ensembl Information

Ensembl Gene ID	Ensembl Protein ID	Ensembl Transcript ID
ENSG00000178568	ENSP00000342235	ENST00000342788
ENSG00000178568	ENSP00000403204	ENST00000436443
ENSG00000178568	ENSP00000260943	ENST00000260943
ENSG00000178568	ENSP00000385565	ENST00000402597
ENSG00000178568	ENSP00000405564	ENST00000435846

Organism

Homo sapiens

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

1308

Protein Sequence
(FASTA)

MKPATGLWVW VSLLVAAGTV QPSDSQSVCA GTENKLSSLS DLEQQYRALR KYYENCEVVM 60

GNLEITSIEH NRDLSFLRSV REVTGYVLVA LNQFRYLPLE NLRIIRGTKL YEDRYALAIF 120

LNYRKDGNFG LQELGLKNLT EILNGGVYVD QNKFLCYADT IHWQDIVRNP WPSNLTLVST 180

NGSSGCGRCH KSCTGRCWGP TENHCQTLTR TVCAEQCDGR CYGPYVSDCC HRECAGGCSG 240

PKDTDCFACM NFNDSGACVT QCPQTFVYNP TTFQLEHNFN AKYTYGAFCV KKCPHNFVVD 300

SSSCVRACPS SKMEVEENGI KMCKPCTDIC PKACDGIGTG SLMSAQTVDS SNIDKFINCT 360

KINGNLIFLV TGIHGDPYNA IEAIDPEKLN VFRTVREITG FLNIQSWPPN MTDFSVFSNL 420

VTIGGRVLYS GLSLLILKQQ GITSLQFQSL KEISAGNIYI TDNSNLCYYH TINWTTLFST 480

INQRIVIRDN RKAENCTAEG MVCNHLCSSD GCWGPGPDQC LSCRRFSRGR ICIESCNLYD 540

GEFREFENGS ICVECDPQCE KMEDGLLTCH GPGPDNCTKC SHFKDGPNCV EKCPDGLQGA 600

NSFIFKYADP DRECHPCHPN CTQGCNGPTS HDCIYYPWTG HSTLPQHART PLIAAGVIGG 660

LFILVIVGLT FAVYVRRKSI KKKRALRRFL ETELVEPLTP SGTAPNQAQL RILKETELKR 720

VKVLGSGAFG TVYKGIWVPE GETVKIPVAI KILNETTGPK ANVEFMDEAL IMASMDHPHL 780

VRLLGVCLSP TIQLVTQLMP HGCLLEYVHE 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 PPPIYTSRAR IDSNRSEIGH SPPPAYTPMS GNQFVYRDGG FAAEQGVSVP 1080

YRAPTSTIPE APVAQGATAE IFDDSCCNGT LRKPVAPHVQ EDSSTQRYSA DPTVFAPERS 1140

PRGELDEEGY MTPMRDKPKQ EYLNPVEENP FVSRRKNGDL QALDNPEYHN ASNGPPKAED 1200

EYVNEPLYLN TFANTLGKAE YLKNNILSMP EKAKKAFDNP DYWNHSLPPR STLQHPDYLQ 1260

EYSTKYFYKQ NGRIRPIVAE NPEYLSEFSL KPGTVLPPPP YRHRNTVV 1308

Nucleotide Sequence
(FASTA)

ATGAAGCCGG CGACAGGACT TTGGGTCTGG GTGAGCCTTC TCGTGGCGGC GGGGACCGTC 60

CAGCCCAGCG ATTCTCAGTC AGTGTGTGCA GGAACGGAGA ATAAACTGAG CTCTCTCTCT 120

GACCTGGAAC AGCAGTACCG AGCCTTGCGC AAGTACTATG AAAACTGTGA GGTTGTCATG 180

GGCAACCTGG AGATAACCAG CATTGAGCAC AACCGGGACC TCTCCTTCCT GCGGTCTGTT 240

CGAGAAGTCA CAGGCTACGT GTTAGTGGCT CTTAATCAGT TTCGTTACCT GCCTCTGGAG 300

AATTTACGCA TTATTCGTGG GACAAAACTT TATGAGGATC GATATGCCTT GGCAATATTT 360

TTAAACTACA GAAAAGATGG AAACTTTGGA CTTCAAGAAC TTGGATTAAA GAACTTGACA 420

GAAATCCTAA ATGGTGGAGT CTATGTAGAC CAGAACAAAT TCCTTTGTTA TGCAGACACC 480

ATTCATTGGC AAGATATTGT TCGGAACCCA TGGCCTTCCA ACTTGACTCT TGTGTCAACA 540

AATGGTAGTT CAGGATGTGG ACGTTGCCAT AAGTCCTGTA CTGGCCGTTG CTGGGGACCC 600

ACAGAAAATC ATTGCCAGAC TTTGACAAGG ACGGTGTGTG CAGAACAATG TGACGGCAGA 660

TGCTACGGAC CTTACGTCAG TGACTGCTGC CATCGAGAAT GTGCTGGAGG CTGCTCAGGA 720

CCTAAGGACA CAGACTGCTT TGCCTGCATG AATTTCAATG ACAGTGGAGC ATGTGTTACT 780

CAGTGTCCCC AAACCTTTGT CTACAATCCA ACCACCTTTC AACTGGAGCA CAATTTCAAT 840

GCAAAGTACA CATATGGAGC ATTCTGTGTC AAGAAATGTC CACATAACTT TGTGGTAGAT 900

TCCAGTTCTT GTGTGCGTGC CTGCCCTAGT TCCAAGATGG AAGTAGAAGA AAATGGGATT 960

AAAATGTGTA AACCTTGCAC TGACATTTGC CCAAAAGCTT GTGATGGCAT TGGCACAGGA 1020

TCATTGATGT CAGCTCAGAC TGTGGATTCC AGTAACATTG ACAAATTCAT AAACTGTACC 1080

AAGATCAATG GGAATTTGAT CTTTCTAGTC ACTGGTATTC ATGGGGACCC TTACAATGCA 1140

ATTGAAGCCA TAGACCCAGA GAAACTGAAC GTCTTTCGGA CAGTCAGAGA GATAACAGGT 1200

TTCCTGAACA TACAGTCATG GCCACCAAAC ATGACTGACT TCAGTGTTTT TTCTAACCTG 1260

GTGACCATTG GTGGAAGAGT ACTCTATAGT GGCCTGTCCT TGCTTATCCT CAAGCAACAG 1320

GGCATCACCT CTCTACAGTT CCAGTCCCTG AAGGAAATCA GCGCAGGAAA CATCTATATT 1380

ACTGACAACA GCAACCTGTG TTATTATCAT ACCATTAACT GGACAACACT CTTCAGCACA 1440

ATCAACCAGA GAATAGTAAT CCGGGACAAC AGAAAAGCTG AAAATTGTAC TGCTGAAGGA 1500

ATGGTGTGCA ACCATCTGTG TTCCAGTGAT GGCTGTTGGG GACCTGGGCC AGACCAATGT 1560

CTGTCGTGTC GCCGCTTCAG TAGAGGAAGG ATCTGCATAG AGTCTTGTAA CCTCTATGAT 1620

GGTGAATTTC GGGAGTTTGA GAATGGCTCC ATCTGTGTGG AGTGTGACCC CCAGTGTGAG 1680

AAGATGGAAG ATGGCCTCCT CACATGCCAT GGACCGGGTC CTGACAACTG TACAAAGTGC 1740

TCTCATTTTA AAGATGGCCC AAACTGTGTG GAAAAATGTC CAGATGGCTT ACAGGGGGCA 1800

AACAGTTTCA TTTTCAAGTA TGCTGATCCA GATCGGGAGT GCCACCCATG CCATCCAAAC 1860

TGCACCCAAG GGTGTAACGG TCCCACTAGT CATGACTGCA TTTACTACCC ATGGACGGGC 1920

CATTCCACTT TACCACAACA TGCTAGAACT CCCCTGATTG CAGCTGGAGT AATTGGTGGG 1980

CTCTTCATTC TGGTCATTGT GGGTCTGACA TTTGCTGTTT ATGTTAGAAG GAAGAGCATC 2040

AAAAAGAAAA GAGCCTTGAG AAGATTCTTG GAAACAGAGT TGGTGGAACC ATTAACTCCC 2100

AGTGGCACAG CACCCAATCA AGCTCAACTT CGTATTTTGA AAGAAACTGA GCTGAAGAGG 2160

GTAAAAGTCC TTGGCTCAGG TGCTTTTGGA ACGGTTTATA AAGGTATTTG GGTACCTGAA 2220

GGAGAAACTG TGAAGATTCC TGTGGCTATT AAGATTCTTA ATGAGACAAC TGGTCCCAAG 2280

GCAAATGTGG AGTTCATGGA TGAAGCTCTG ATCATGGCAA GTATGGATCA TCCACACCTA 2340

GTCCGGTTGC TGGGTGTGTG TCTGAGCCCA ACCATCCAGC TGGTTACTCA ACTTATGCCC 2400

CATGGCTGCC TGTTGGAGTA TGTCCACGAG CACAAGGATA ACATTGGATC ACAACTGCTG 2460

CTTAACTGGT GTGTCCAGAT AGCTAAGGGA ATGATGTACC TGGAAGAAAG ACGACTCGTT 2520

CATCGGGATT TGGCAGCCCG TAATGTCTTA GTGAAATCTC CAAACCATGT GAAAATCACA 2580

GATTTTGGGC TAGCCAGACT CTTGGAAGGA GATGAAAAAG AGTACAATGC TGATGGAGGA 2640

AAGATGCCAA TTAAATGGAT GGCTCTGGAG TGTATACATT ACAGGAAATT CACCCATCAG 2700

AGTGACGTTT GGAGCTATGG AGTTACTATA TGGGAACTGA TGACCTTTGG AGGAAAACCC 2760

TATGATGGAA TTCCAACGCG AGAAATCCCT GATTTATTAG AGAAAGGAGA ACGTTTGCCT 2820

CAGCCTCCCA TCTGCACTAT TGACGTTTAC ATGGTCATGG TCAAATGTTG GATGATTGAT 2880

GCTGACAGTA GACCTAAATT TAAGGAACTG GCTGCTGAGT TTTCAAGGAT GGCTCGAGAC 2940

CCTCAAAGAT ACCTAGTTAT TCAGGGTGAT GATCGTATGA AGCTTCCCAG TCCAAATGAC 3000

AGCAAGTTCT TTCAGAATCT CTTGGATGAA GAGGATTTGG AAGATATGAT GGATGCTGAG 3060

GAGTACTTGG TCCCTCAGGC TTTCAACATC CCACCTCCCA TCTATACTTC CAGAGCAAGA 3120

ATTGACTCGA ATAGGAGTGA AATTGGACAC AGCCCTCCTC CTGCCTACAC CCCCATGTCA 3180

GGAAACCAGT TTGTATACCG AGATGGAGGT TTTGCTGCTG AACAAGGAGT GTCTGTGCCC 3240

TACAGAGCCC CAACTAGCAC AATTCCAGAA GCTCCTGTGG CACAGGGTGC TACTGCTGAG 3300

ATTTTTGATG ACTCCTGCTG TAATGGCACC CTACGCAAGC CAGTGGCACC CCATGTCCAA 3360

GAGGACAGTA GCACCCAGAG GTACAGTGCT GACCCCACCG TGTTTGCCCC AGAACGGAGC 3420

CCACGAGGAG AGCTGGATGA GGAAGGTTAC ATGACTCCTA TGCGAGACAA ACCCAAACAA 3480

GAATACCTGA ATCCAGTGGA GGAGAACCCT TTTGTTTCTC GGAGAAAAAA TGGAGACCTT 3540

CAAGCATTGG ATAATCCCGA ATATCACAAT GCATCCAATG GTCCACCCAA GGCCGAGGAT 3600

GAGTATGTGA ATGAGCCACT GTACCTCAAC ACCTTTGCCA ACACCTTGGG AAAAGCTGAG 3660

TACCTGAAGA ACAACATACT GTCAATGCCA GAGAAGGCCA AGAAAGCGTT TGACAACCCT 3720

GACTACTGGA ACCACAGCCT GCCACCTCGG AGCACCCTTC AGCACCCAGA CTACCTGCAG 3780

GAGTACAGCA CAAAATATTT TTATAAACAG AATGGGCGGA TCCGGCCTAT TGTGGCAGAG 3840

AATCCTGAAT ACCTCTCTGA GTTCTCCCTG AAGCCAGGCA CTGTGCTGCC GCCTCCACCT 3900

TACAGACACC GGAATACTGT GGTGTAA 3927

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+Gcll+yv+ehkd++Gsq llnwcvqiakGm+ylee+

Q: 778   PHLVRLLGVCLSPTIQLVTQLMPHGCLLEYVHEHKDNIGSQLLLNWCVQIAKGMMYLEER  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 LMPHGCLLEY VHEHKDNIGS QLLLNWCVQI AKGMMYLEER 120

RLVHRDLAAR NVLVKSPNHV KITDFGLARL LEGDEKEYNA DGGKMPIKWM ALECIHYRKF 180

THQSDVWSYG VTIWELMTFG GKPYDGIPTR EIPDLLEKGE RLPQPPICTI DVYMVMVKCW 240

MIDADSRPKF KELAAEFS 258

Keyword

3D-structure; Activator; Alternative splicing; Apoptosis; ATP-binding; Cell membrane; Complete proteome; Developmental protein; Disulfide bond; Glycoprotein; Kinase; Lactation; Membrane; Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism; 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"; ?>Ciona savignyi"; ?>Danio rerio"; ?>Drosophila melanogaster"; ?>Equus caballus"; ?>Gadus morhua"; ?>Gallus gallus"; ?>Gasterosteus aculeatus"; ?>Gorilla gorilla"; ?>Ictidomys tridecemlineatus"; ?>Latimeria chalumnae"; ?>Loxodonta africana"; ?>Macaca mulatta"; ?>Meleagris gallopavo"; ?>Monodelphis domestica"; ?>Mus musculus"; ?>Mustela putorius furo"; ?>Myotis lucifugus"; ?>Nomascus leucogenys"; ?>Ochotona princeps"; ?>Oreochromis niloticus"; ?>Ornithorhynchus anatinus"; ?>Oryctolagus cuniculus"; ?>Oryzias latipes"; ?>Otolemur garnettii"; ?>Pan troglodytes"; ?>Pelodiscus sinensis"; ?>Petromyzon marinus"; ?>Pongo abelii"; ?>Pteropus vampyrus"; ?>Rattus norvegicus"; ?>Sarcophilus harrisii"; ?>Sus scrofa"; ?>Taeniopygia guttata"; ?>Takifugu rubripes"; ?>Tetraodon nigroviridis"; ?>Tursiops truncatus"; ?>Vicugna pacos"; ?>Xenopus tropicalis"; ?>Xiphophorus maculatus"; ?>

Gene Ontology

GO:0016323	; C:basolateral plasma membrane
GO:0005901	; C:caveola
GO:0005829	; C:cytosol
GO:0005576	; C:extracellular region
GO:0016021	; C:integral to membrane
GO:0005759	; C:mitochondrial matrix
GO:0005654	; C:nucleoplasm
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:0008283	; P:cell proliferation
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

hsa:2066

;

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