EPB4A_DANRE
ID EPB4A_DANRE Reviewed; 987 AA.
AC O73875; A0A2R8QG60;
DT 05-JUN-2019, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 3.
DT 03-AUG-2022, entry version 167.
DE RecName: Full=Ephrin type-B receptor 4a {ECO:0000250|UniProtKB:P54760};
DE EC=2.7.10.1 {ECO:0000255|PROSITE-ProRule:PRU00159};
DE AltName: Full=Eph receptor B4a {ECO:0000312|ZFIN:ZDB-GENE-990415-62};
DE AltName: Full=Eph-like receptor tyrosine kinase rtk5 {ECO:0000312|EMBL:CAA06299.2};
DE Flags: Precursor;
GN Name=ephb4a {ECO:0000312|ZFIN:ZDB-GENE-990415-62};
GN Synonyms=rtk5 {ECO:0000303|PubMed:27747378};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=27747378; DOI=10.1007/s004270050082;
RA Cooke J.E., Xu Q., Wilson S.W., Holder N.;
RT "Characterisation of five novel zebrafish Eph-related receptor tyrosine
RT kinases suggests roles in patterning the neural plate.";
RL Dev. Genes Evol. 206:515-531(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [3]
RP FUNCTION.
RX PubMed=9765210; DOI=10.1101/gad.12.19.3096;
RA Durbin L., Brennan C., Shiomi K., Cooke J., Barrios A., Shanmugalingam S.,
RA Guthrie B., Lindberg R., Holder N.;
RT "Eph signaling is required for segmentation and differentiation of the
RT somites.";
RL Genes Dev. 12:3096-3109(1998).
RN [4]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=29444212; DOI=10.1093/brain/awy020;
RA Vivanti A., Ozanne A., Grondin C., Saliou G., Quevarec L., Maurey H.,
RA Aubourg P., Benachi A., Gut M., Gut I., Martinovic J., Senat M.V., Tawk M.,
RA Melki J.;
RT "Loss of function mutations in EPHB4 are responsible for vein of Galen
RT aneurysmal malformation.";
RL Brain 141:979-988(2018).
CC -!- FUNCTION: Receptor tyrosine kinase which binds promiscuously
CC transmembrane ephrin-B family ligands residing on adjacent cells,
CC leading to contact-dependent bidirectional signaling into neighboring
CC cells. The signaling pathway downstream of the receptor is referred to
CC as forward signaling while the signaling pathway downstream of the
CC ephrin ligand is referred to as reverse signaling. Together with its
CC cognate ligand/functional ligand EFNB2 is involved in the regulation of
CC cell adhesion and cell migration, and plays a central role in heart
CC morphogenesis, angiogenesis and blood vessel remodeling and
CC permeability (PubMed:29444212). EPHB4-mediated forward signaling
CC controls cellular repulsion and segregation from EFNB2-expressing cells
CC (By similarity) (PubMed:29444212). Involved in somitogenesis
CC (PubMed:9765210). {ECO:0000250|UniProtKB:P54760,
CC ECO:0000269|PubMed:29444212, ECO:0000269|PubMed:9765210}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-tyrosyl-[protein] = ADP + H(+) + O-phospho-L-tyrosyl-
CC [protein]; Xref=Rhea:RHEA:10596, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC COMP:10137, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:46858,
CC ChEBI:CHEBI:82620, ChEBI:CHEBI:456216; EC=2.7.10.1;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU00159};
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P54760};
CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:P54760}.
CC -!- DISRUPTION PHENOTYPE: Morpholino knockdown of the protein results in
CC marked vascular anomalies of the dorsal cranial vessels including both
CC dorsal longitudinal and mesencephalic veins.
CC {ECO:0000269|PubMed:29444212}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Ephrin receptor subfamily. {ECO:0000255|PROSITE-
CC ProRule:PRU00159}.
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DR EMBL; AJ005026; CAA06299.2; -; mRNA.
DR EMBL; CABZ01093042; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; FO904976; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CABZ01093043; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CABZ01112153; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CABZ01112154; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CABZ01112155; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CABZ01112156; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CABZ01112157; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CU682352; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CU928075; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_571489.1; NM_131414.1.
DR AlphaFoldDB; O73875; -.
DR SMR; O73875; -.
DR STRING; 7955.ENSDARP00000111946; -.
DR Ensembl; ENSDART00000187955; ENSDARP00000152897; ENSDARG00000100725.
DR GeneID; 30688; -.
DR KEGG; dre:30688; -.
DR CTD; 30688; -.
DR ZFIN; ZDB-GENE-990415-62; ephb4a.
DR GeneTree; ENSGT00940000166305; -.
DR OrthoDB; 933071at2759; -.
DR PhylomeDB; O73875; -.
DR Reactome; R-DRE-2682334; EPH-Ephrin signaling.
DR Reactome; R-DRE-3928662; EPHB-mediated forward signaling.
DR Reactome; R-DRE-3928664; Ephrin signaling.
DR Reactome; R-DRE-3928665; EPH-ephrin mediated repulsion of cells.
DR PRO; PR:O73875; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 5.
DR Bgee; ENSDARG00000100725; Expressed in chordate pharynx and 68 other tissues.
DR ExpressionAtlas; O73875; baseline and differential.
DR GO; GO:0005887; C:integral component of plasma membrane; IEA:InterPro.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005003; F:ephrin receptor activity; IEA:InterPro.
DR GO; GO:0035475; P:angioblast cell migration involved in selective angioblast sprouting; IMP:ZFIN.
DR GO; GO:0001568; P:blood vessel development; IMP:ZFIN.
DR GO; GO:0060026; P:convergent extension; IGI:ZFIN.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; IGI:ZFIN.
DR GO; GO:0001945; P:lymph vessel development; IMP:ZFIN.
DR GO; GO:0048845; P:venous blood vessel morphogenesis; IMP:ZFIN.
DR CDD; cd10474; EphR_LBD_B4; 1.
DR CDD; cd00063; FN3; 2.
DR CDD; cd09554; SAM_EPH-B4; 1.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR037636; EPH-B4_SAM.
DR InterPro; IPR027936; Eph_TM.
DR InterPro; IPR034290; EphB4_rcpt_lig-bd.
DR InterPro; IPR001090; Ephrin_rcpt_lig-bd_dom.
DR InterPro; IPR003961; FN3_dom.
DR InterPro; IPR036116; FN3_sf.
DR InterPro; IPR008979; Galactose-bd-like_sf.
DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed_sf.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016257; Tyr_kinase_ephrin_rcpt.
DR InterPro; IPR001426; Tyr_kinase_rcpt_V_CS.
DR Pfam; PF14575; EphA2_TM; 1.
DR Pfam; PF01404; Ephrin_lbd; 1.
DR Pfam; PF00041; fn3; 2.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF00536; SAM_1; 1.
DR PIRSF; PIRSF000666; TyrPK_ephrin_receptor; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00615; EPH_lbd; 1.
DR SMART; SM00060; FN3; 2.
DR SMART; SM00454; SAM; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR SUPFAM; SSF57184; SSF57184; 1.
DR PROSITE; PS01186; EGF_2; 1.
DR PROSITE; PS51550; EPH_LBD; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00791; RECEPTOR_TYR_KIN_V_2; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
PE 2: Evidence at transcript level;
KW ATP-binding; Cell membrane; Disulfide bond; Kinase; Membrane;
KW Nucleotide-binding; Receptor; Reference proteome; Repeat; Signal;
KW Transferase; Transmembrane; Transmembrane helix; Tyrosine-protein kinase.
FT SIGNAL 1..24
FT /evidence="ECO:0000255"
FT CHAIN 25..987
FT /note="Ephrin type-B receptor 4a"
FT /evidence="ECO:0000255"
FT /id="PRO_5004159945"
FT TOPO_DOM 25..548
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 549..569
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 570..987
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 26..205
FT /note="Eph LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00883"
FT DOMAIN 328..438
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 442..536
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 621..884
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 914..978
FT /note="SAM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT REGION 319..340
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 746
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 627..635
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 653
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DISULFID 70..187
FT /evidence="ECO:0000250|UniProtKB:P54760"
FT DISULFID 104..114
FT /evidence="ECO:0000250|UniProtKB:P54760"
FT CONFLICT 13
FT /note="I -> V (in Ref. 1; CAA06299)"
FT CONFLICT 79..80
FT /note="WL -> CV (in Ref. 1; CAA06299)"
FT CONFLICT 852
FT /note="P -> S (in Ref. 1; CAA06299)"
SQ SEQUENCE 987 AA; 109669 MW; 6AF62CF885DF9FA4 CRC64;
MELFSRNVAA FWIILLEFLL GSVAEEEVLM NTKTETSDLK WTTHSRSKPE WEEVSGLDEE
NNSVRTYQIC QADGSSSHWL RSKLIERRGA SQVYVELFFT MVECSSRNTH HRSCKETFNL
YYYQSDTDDA TATHPAWMEN PYTKVDTVAA DFLLRKGGEK KVNVKTLRLG PLSKRGFYLA
FQAQGACMAL LSVRVFFKKC PALTRSLSVF PETVPRSLVQ EAVGQCVANA AQPGPSPRPP
KMFCGEDGQW VDQPTTTCTC LPGFEASHGE LECRACPVGL FKMGSGTGPC SVCPENSQTG
ETGSAACVCR SGFYRALSDS ADTPCTRPPS SPRSPVPQVN DTSLTLEWSE PLDSGGRSDL
SYSVECRMCS TPGSPCTLCS DGVNYRPSQT GIQGRRVSIW GLRPHTTYSF TVMALNGVSA
QSQQGPAGET INITTSPNVP VLVSGLRKST ATESSLTLYW NTPTQSHYRI LQYQIRYCEK
ERGSEENSCH YMESNNNEVV LSDLRRATQY EVQVRARTFA GYGSFGKAIL FRTLPDEDDS
SSPLLVTGIL IAMGMLLLII VIGAAIYCIR KQNNYKDPEL SDKNGQYLMG QGVKVYIDPF
TYEDPNEAVR EFAKEIDVSC VKIEEVIGAG EFGEVCRGRL RIPGKKENYV AIKTLKGGYT
DKQRRDFLAE ASIMGQFQHP NIIHLEGIIT ASCPVMILTE FMENGALDSF LRLNDGQFTP
IQLVGMLRGI ASGMKYLSEM SYVHRDLAAR NILVNSNLVC KVSDFGLSRF LQENSSDPTY
TSSLGGKIPI RWTAPEAIAF RKFTCASDVW SYGIVMWEVM SFGERPYWDM SNQDVINAIE
QDYRLPPPPD CPTYLHQLML DCWQKERTAR PRFANIVSAL DKLIRNPASL KITAQEGAGP
SHPLLDQRSP LTPSSCGTVG DWLRAIKMER YEETFLQAGY TSMQLVTHIN TEDLLRLGIT
LAGHQKKILS SIEALGIQNK APGNVLY
