EPHA4_HUMAN
ID EPHA4_HUMAN Reviewed; 986 AA.
AC P54764; A8K2P1; B2R601; B7Z6Q8; Q2M380;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 216.
DE RecName: Full=Ephrin type-A receptor 4;
DE EC=2.7.10.1;
DE AltName: Full=EPH-like kinase 8;
DE Short=EK8;
DE Short=hEK8;
DE AltName: Full=Tyrosine-protein kinase TYRO1;
DE AltName: Full=Tyrosine-protein kinase receptor SEK;
DE Flags: Precursor;
GN Name=EPHA4; Synonyms=HEK8, SEK, TYRO1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Fetal brain;
RX PubMed=7898931;
RA Fox G.M., Holst P.L., Chute H.T., Lindberg R.A., Janssen A.M., Basu R.,
RA Welcher A.A.;
RT "cDNA cloning and tissue distribution of five human EPH-like receptor
RT protein-tyrosine kinases.";
RL Oncogene 10:897-905(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Amygdala, and Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP NOMENCLATURE.
RX PubMed=9267020; DOI=10.1016/s0092-8674(00)80500-0;
RG Eph nomenclature committee;
RT "Unified nomenclature for Eph family receptors and their ligands, the
RT ephrins.";
RL Cell 90:403-404(1997).
RN [6]
RP INTERACTION WITH SIPA1L1.
RX PubMed=18094260; DOI=10.1523/jneurosci.2746-07.2007;
RA Richter M., Murai K.K., Bourgin C., Pak D.T., Pasquale E.B.;
RT "The EphA4 receptor regulates neuronal morphology through SPAR-mediated
RT inactivation of Rap GTPases.";
RL J. Neurosci. 27:14205-14215(2007).
RN [7]
RP FUNCTION IN PHOSPHORYLATION OF CDK5, AND AUTOPHOSPHORYLATION.
RX PubMed=17143272; DOI=10.1038/nn1811;
RA Fu W.Y., Chen Y., Sahin M., Zhao X.S., Shi L., Bikoff J.B., Lai K.O.,
RA Yung W.H., Fu A.K., Greenberg M.E., Ip N.Y.;
RT "Cdk5 regulates EphA4-mediated dendritic spine retraction through an
RT ephexin1-dependent mechanism.";
RL Nat. Neurosci. 10:67-76(2007).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19369195; DOI=10.1074/mcp.m800588-mcp200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 29-209.
RX PubMed=18708347; DOI=10.1074/jbc.m804114200;
RA Qin H., Shi J., Noberini R., Pasquale E.B., Song J.;
RT "Crystal structure and NMR binding reveal that two small molecule
RT antagonists target the high affinity ephrin-binding channel of the EphA4
RT receptor.";
RL J. Biol. Chem. 283:29473-29484(2008).
RN [10]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 30-202 IN COMPLEX WITH EFNA2 OR
RP EFNB2, AND LIGAND-BINDING.
RX PubMed=19836338; DOI=10.1016/j.str.2009.07.018;
RA Bowden T.A., Aricescu A.R., Nettleship J.E., Siebold C., Rahman-Huq N.,
RA Owens R.J., Stuart D.I., Jones E.Y.;
RT "Structural plasticity of EPH receptor A4 facilitates cross-class ephrin
RT signaling.";
RL Structure 17:1386-1397(2009).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 29-203 IN COMPLEX WITH EFNB2, AND
RP MUTAGENESIS OF GLN-40 AND GLU-42.
RX PubMed=19875447; DOI=10.1074/jbc.m109.064824;
RA Qin H., Noberini R., Huan X., Shi J., Pasquale E.B., Song J.;
RT "Structural characterization of the EphA4-Ephrin-B2 complex reveals new
RT features enabling Eph-ephrin binding promiscuity.";
RL J. Biol. Chem. 285:644-654(2010).
RN [12]
RP VARIANTS [LARGE SCALE ANALYSIS] GLN-269; GLU-370 AND PHE-399.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G.,
RA Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S.,
RA Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G.,
RA Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K.,
RA Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D.,
RA Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R.,
RA Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A.,
RA Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F.,
RA Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F.,
RA Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G.,
RA Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R.,
RA Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Receptor tyrosine kinase which binds membrane-bound ephrin
CC family ligands residing on adjacent cells, leading to contact-dependent
CC bidirectional signaling into neighboring cells. The signaling pathway
CC downstream of the receptor is referred to as forward signaling while
CC the signaling pathway downstream of the ephrin ligand is referred to as
CC reverse signaling. Highly promiscuous, it has the unique property among
CC Eph receptors to bind and to be physiologically activated by both GPI-
CC anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1
CC and EFNB3. Upon activation by ephrin ligands, modulates cell morphology
CC and integrin-dependent cell adhesion through regulation of the Rac, Rap
CC and Rho GTPases activity. Plays an important role in the development of
CC the nervous system controlling different steps of axonal guidance
CC including the establishment of the corticospinal projections. May also
CC control the segregation of motor and sensory axons during neuromuscular
CC circuit development. In addition to its role in axonal guidance plays a
CC role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at
CC 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and
CC dendritic spine morphogenesis. In the nervous system, also plays a role
CC in repair after injury preventing axonal regeneration and in
CC angiogenesis playing a role in central nervous system vascular
CC formation. Additionally, its promiscuity makes it available to
CC participate in a variety of cell-cell signaling regulating for instance
CC the development of the thymic epithelium. During development of the
CC cochlear organ of Corti, regulates pillar cell separation by forming a
CC ternary complex with ADAM10 and CADH1 which facilitates the cleavage of
CC CADH1 by ADAM10 and disruption of adherens junctions (By similarity).
CC {ECO:0000250|UniProtKB:Q03137, ECO:0000269|PubMed:17143272}.
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:PRU10028};
CC -!- SUBUNIT: Heterotetramer upon binding of the ligand. The heterotetramer
CC is composed of an ephrin dimer and a receptor dimer. Oligomerization is
CC probably required to induce biological responses. Interacts
CC (phosphorylated at position Tyr-602) with FYN. Interacts with CDK5,
CC CDK5R1 and NGEF; upon activation by EFNA1 induces NGEF phosphorylation
CC by the kinase CDK5. Interacts with CHN1; effector of EPHA4 in axon
CC guidance linking EPHA4 activation to RAC1 regulation (By similarity).
CC Interacts (via PDZ motif) with SIPA1L1 (via PDZ domain); controls
CC neuronal morphology through regulation of the RAP1 (RAP1A or RAP1B) and
CC RAP2 (RAP2A, RAP2B or RAP2C) GTPases. Forms a ternary complex composed
CC of ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by
CC ADAM10 which disrupts adherens junctions (By similarity). {ECO:0000250,
CC ECO:0000250|UniProtKB:Q03137, ECO:0000269|PubMed:18094260,
CC ECO:0000269|PubMed:19836338, ECO:0000269|PubMed:19875447}.
CC -!- INTERACTION:
CC P54764; O43921: EFNA2; NbExp=4; IntAct=EBI-5773557, EBI-8603210;
CC P54764; P52803: EFNA5; NbExp=2; IntAct=EBI-5773557, EBI-1753674;
CC P54764; P52799: EFNB2; NbExp=4; IntAct=EBI-5773557, EBI-7532268;
CC P54764; Q15768: EFNB3; NbExp=2; IntAct=EBI-5773557, EBI-3908475;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I
CC membrane protein {ECO:0000250}. Cell projection, axon {ECO:0000250}.
CC Cell projection, dendrite {ECO:0000250}. Postsynaptic density membrane
CC {ECO:0000250}. Early endosome {ECO:0000250}. Cell junction, adherens
CC junction {ECO:0000250|UniProtKB:Q03137}. Note=Clustered upon activation
CC and targeted to early endosome. {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P54764-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P54764-2; Sequence=VSP_056016;
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- DOMAIN: The protein kinase domain mediates interaction with NGEF.
CC {ECO:0000250}.
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; L36645; AAA74246.1; -; mRNA.
DR EMBL; AK290306; BAF82995.1; -; mRNA.
DR EMBL; AK300772; BAH13344.1; -; mRNA.
DR EMBL; AK312380; BAG35298.1; -; mRNA.
DR EMBL; AC010899; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC079834; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC105000; AAI05001.1; -; mRNA.
DR EMBL; BC105002; AAI05003.1; -; mRNA.
DR CCDS; CCDS2447.1; -. [P54764-1]
DR PIR; I78844; I78844.
DR RefSeq; NP_001291465.1; NM_001304536.1. [P54764-1]
DR RefSeq; NP_001291466.1; NM_001304537.1. [P54764-2]
DR RefSeq; NP_004429.1; NM_004438.4. [P54764-1]
DR PDB; 2LW8; NMR; -; A=29-209.
DR PDB; 2WO1; X-ray; 1.85 A; A/B=30-202.
DR PDB; 2WO2; X-ray; 2.45 A; A=30-202.
DR PDB; 2WO3; X-ray; 2.35 A; A=30-202.
DR PDB; 3CKH; X-ray; 2.80 A; A/B=29-209.
DR PDB; 3GXU; X-ray; 2.50 A; A=29-203.
DR PDB; 4BK4; X-ray; 3.65 A; A/B=20-547.
DR PDB; 4BK5; X-ray; 4.00 A; A=20-547.
DR PDB; 4BKA; X-ray; 5.30 A; A=20-547.
DR PDB; 4BKF; X-ray; 4.65 A; A/B=20-547.
DR PDB; 4M4P; X-ray; 2.08 A; A=27-543.
DR PDB; 4M4R; X-ray; 3.13 A; A/C/E/G=27-543.
DR PDB; 4W4Z; X-ray; 2.41 A; A/B/C/D=29-204.
DR PDB; 4W50; X-ray; 2.42 A; A/B/C/D=29-204.
DR PDB; 5JR2; X-ray; 1.75 A; A/B/C/D=29-204.
DR PDB; 7OFV; X-ray; 1.43 A; A=29-209.
DR PDBsum; 2LW8; -.
DR PDBsum; 2WO1; -.
DR PDBsum; 2WO2; -.
DR PDBsum; 2WO3; -.
DR PDBsum; 3CKH; -.
DR PDBsum; 3GXU; -.
DR PDBsum; 4BK4; -.
DR PDBsum; 4BK5; -.
DR PDBsum; 4BKA; -.
DR PDBsum; 4BKF; -.
DR PDBsum; 4M4P; -.
DR PDBsum; 4M4R; -.
DR PDBsum; 4W4Z; -.
DR PDBsum; 4W50; -.
DR PDBsum; 5JR2; -.
DR PDBsum; 7OFV; -.
DR AlphaFoldDB; P54764; -.
DR SMR; P54764; -.
DR BioGRID; 108357; 80.
DR DIP; DIP-48294N; -.
DR IntAct; P54764; 68.
DR MINT; P54764; -.
DR STRING; 9606.ENSP00000281821; -.
DR BindingDB; P54764; -.
DR ChEMBL; CHEMBL3988; -.
DR DrugBank; DB12010; Fostamatinib.
DR DrugCentral; P54764; -.
DR GuidetoPHARMACOLOGY; 1824; -.
DR GlyGen; P54764; 4 sites.
DR iPTMnet; P54764; -.
DR PhosphoSitePlus; P54764; -.
DR BioMuta; EPHA4; -.
DR DMDM; 1711371; -.
DR CPTAC; CPTAC-2790; -.
DR EPD; P54764; -.
DR jPOST; P54764; -.
DR MassIVE; P54764; -.
DR MaxQB; P54764; -.
DR PaxDb; P54764; -.
DR PeptideAtlas; P54764; -.
DR PRIDE; P54764; -.
DR ProteomicsDB; 56717; -. [P54764-1]
DR TopDownProteomics; P54764-1; -. [P54764-1]
DR ABCD; P54764; 11 sequenced antibodies.
DR Antibodypedia; 34350; 703 antibodies from 38 providers.
DR DNASU; 2043; -.
DR Ensembl; ENST00000281821.7; ENSP00000281821.2; ENSG00000116106.12. [P54764-1]
DR Ensembl; ENST00000409938.5; ENSP00000386829.1; ENSG00000116106.12. [P54764-1]
DR GeneID; 2043; -.
DR KEGG; hsa:2043; -.
DR MANE-Select; ENST00000281821.7; ENSP00000281821.2; NM_004438.5; NP_004429.1.
DR UCSC; uc002vmq.4; human. [P54764-1]
DR CTD; 2043; -.
DR DisGeNET; 2043; -.
DR GeneCards; EPHA4; -.
DR HGNC; HGNC:3388; EPHA4.
DR HPA; ENSG00000116106; Tissue enhanced (choroid).
DR MalaCards; EPHA4; -.
DR MIM; 602188; gene.
DR neXtProt; NX_P54764; -.
DR OpenTargets; ENSG00000116106; -.
DR Orphanet; 803; Amyotrophic lateral sclerosis.
DR PharmGKB; PA27820; -.
DR VEuPathDB; HostDB:ENSG00000116106; -.
DR eggNOG; KOG0196; Eukaryota.
DR GeneTree; ENSGT00940000156948; -.
DR InParanoid; P54764; -.
DR OMA; TENSRPN; -.
DR PhylomeDB; P54764; -.
DR TreeFam; TF315608; -.
DR BRENDA; 2.7.10.1; 2681.
DR PathwayCommons; P54764; -.
DR Reactome; R-HSA-2682334; EPH-Ephrin signaling.
DR Reactome; R-HSA-3928663; EPHA-mediated growth cone collapse.
DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells.
DR SignaLink; P54764; -.
DR SIGNOR; P54764; -.
DR BioGRID-ORCS; 2043; 17 hits in 1108 CRISPR screens.
DR ChiTaRS; EPHA4; human.
DR EvolutionaryTrace; P54764; -.
DR GeneWiki; EPH_receptor_A4; -.
DR GenomeRNAi; 2043; -.
DR Pharos; P54764; Tchem.
DR PRO; PR:P54764; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P54764; protein.
DR Bgee; ENSG00000116106; Expressed in Brodmann (1909) area 23 and 186 other tissues.
DR ExpressionAtlas; P54764; baseline and differential.
DR Genevisible; P54764; HS.
DR GO; GO:0005912; C:adherens junction; IEA:UniProtKB-SubCell.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0043679; C:axon terminus; IEA:Ensembl.
DR GO; GO:0044295; C:axonal growth cone; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0043198; C:dendritic shaft; ISS:ARUK-UCL.
DR GO; GO:0043197; C:dendritic spine; ISS:ARUK-UCL.
DR GO; GO:0031901; C:early endosome membrane; ISS:UniProtKB.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0030175; C:filopodium; IEA:Ensembl.
DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0099055; C:integral component of postsynaptic membrane; IEA:Ensembl.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:Ensembl.
DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl.
DR GO; GO:0043005; C:neuron projection; IBA:GO_Central.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0098839; C:postsynaptic density membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl.
DR GO; GO:0001540; F:amyloid-beta binding; TAS:ARUK-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0097161; F:DH domain binding; IDA:UniProtKB.
DR GO; GO:0046875; F:ephrin receptor binding; IEA:Ensembl.
DR GO; GO:0005004; F:GPI-linked ephrin receptor activity; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0016301; F:kinase activity; IGI:ARUK-UCL.
DR GO; GO:0042731; F:PH domain binding; IPI:UniProtKB.
DR GO; GO:0004672; F:protein kinase activity; IDA:UniProtKB.
DR GO; GO:1990782; F:protein tyrosine kinase binding; IPI:ARUK-UCL.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0005005; F:transmembrane-ephrin receptor activity; ISS:UniProtKB.
DR GO; GO:0034332; P:adherens junction organization; IEA:Ensembl.
DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl.
DR GO; GO:0007411; P:axon guidance; IBA:GO_Central.
DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR GO; GO:1904646; P:cellular response to amyloid-beta; ISS:ARUK-UCL.
DR GO; GO:0090102; P:cochlea development; IEA:Ensembl.
DR GO; GO:0021957; P:corticospinal tract morphogenesis; ISS:UniProtKB.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; IGI:ARUK-UCL.
DR GO; GO:0097156; P:fasciculation of motor neuron axon; ISS:UniProtKB.
DR GO; GO:0097155; P:fasciculation of sensory neuron axon; ISS:UniProtKB.
DR GO; GO:0008347; P:glial cell migration; IEA:Ensembl.
DR GO; GO:0008045; P:motor neuron axon guidance; ISS:UniProtKB.
DR GO; GO:0048681; P:negative regulation of axon regeneration; ISS:UniProtKB.
DR GO; GO:0007162; P:negative regulation of cell adhesion; IMP:ARUK-UCL.
DR GO; GO:0030336; P:negative regulation of cell migration; IMP:ARUK-UCL.
DR GO; GO:1900038; P:negative regulation of cellular response to hypoxia; IMP:ARUK-UCL.
DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; IMP:ARUK-UCL.
DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; IDA:ARUK-UCL.
DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; ISS:ARUK-UCL.
DR GO; GO:0010977; P:negative regulation of neuron projection development; ISS:ARUK-UCL.
DR GO; GO:1903051; P:negative regulation of proteolysis involved in protein catabolic process; IGI:ARUK-UCL.
DR GO; GO:0072178; P:nephric duct morphogenesis; IEA:Ensembl.
DR GO; GO:0106030; P:neuron projection fasciculation; ISS:ARUK-UCL.
DR GO; GO:0097485; P:neuron projection guidance; ISS:ARUK-UCL.
DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; IDA:UniProtKB.
DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; IGI:ARUK-UCL.
DR GO; GO:1902961; P:positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process; IGI:ARUK-UCL.
DR GO; GO:0045785; P:positive regulation of cell adhesion; IMP:ARUK-UCL.
DR GO; GO:0030335; P:positive regulation of cell migration; IDA:ARUK-UCL.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; IGI:ARUK-UCL.
DR GO; GO:0050775; P:positive regulation of dendrite morphogenesis; IEA:Ensembl.
DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IEA:Ensembl.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; ISS:ARUK-UCL.
DR GO; GO:2001108; P:positive regulation of Rho guanyl-nucleotide exchange factor activity; IDA:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0050821; P:protein stabilization; IGI:ARUK-UCL.
DR GO; GO:0048710; P:regulation of astrocyte differentiation; ISS:UniProtKB.
DR GO; GO:0050770; P:regulation of axonogenesis; ISS:UniProtKB.
DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; ISS:UniProtKB.
DR GO; GO:0043087; P:regulation of GTPase activity; ISS:UniProtKB.
DR GO; GO:1905244; P:regulation of modification of synaptic structure; ISS:ARUK-UCL.
DR GO; GO:0098883; P:synapse pruning; IEA:Ensembl.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR CDD; cd10482; EphR_LBD_A4; 1.
DR CDD; cd00063; FN3; 2.
DR CDD; cd09545; SAM_EPH-A4; 1.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR027936; Eph_TM.
DR InterPro; IPR034270; EphA4_rcpt_lig-bd.
DR InterPro; IPR030602; EphA4_SAM.
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; 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; PF07647; SAM_2; 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; SM00220; S_TKc; 1.
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 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; PS00790; RECEPTOR_TYR_KIN_V_1; 1.
DR PROSITE; PS00791; RECEPTOR_TYR_KIN_V_2; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; ATP-binding; Cell adhesion;
KW Cell junction; Cell membrane; Cell projection; Developmental protein;
KW Endosome; Glycoprotein; Kinase; Membrane; Neurogenesis; Nucleotide-binding;
KW Phosphoprotein; Postsynaptic cell membrane; Receptor; Reference proteome;
KW Repeat; Signal; Synapse; Transferase; Transmembrane; Transmembrane helix;
KW Tyrosine-protein kinase.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..986
FT /note="Ephrin type-A receptor 4"
FT /id="PRO_0000016807"
FT TOPO_DOM 20..547
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 548..569
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 570..986
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 30..209
FT /note="Eph LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00883"
FT DOMAIN 328..439
FT /note="Fibronectin type-III 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 440..537
FT /note="Fibronectin type-III 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 621..882
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 911..975
FT /note="SAM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT MOTIF 984..986
FT /note="PDZ-binding"
FT /evidence="ECO:0000255"
FT ACT_SITE 746
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
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 MOD_RES 596
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q03137"
FT MOD_RES 602
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250|UniProtKB:Q03137"
FT MOD_RES 779
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000255"
FT MOD_RES 928
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000255"
FT CARBOHYD 235
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 340
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 408
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 545
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT VAR_SEQ 1..53
FT /note="MAGIFYFALFSCLFGICDAVTGSRVYPANEVTLLDSRSVQGELGWIASPLEG
FT G -> MK (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_056016"
FT VARIANT 269
FT /note="R -> Q (in dbSNP:rs35084379)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042135"
FT VARIANT 370
FT /note="G -> E (in a bladder carcinoma NOS sample; somatic
FT mutation; dbSNP:rs756952113)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042136"
FT VARIANT 399
FT /note="S -> F (in a metastatic melanoma sample; somatic
FT mutation; dbSNP:rs868224085)"
FT /evidence="ECO:0000269|PubMed:17344846"
FT /id="VAR_042137"
FT VARIANT 953
FT /note="R -> K (in dbSNP:rs35341687)"
FT /id="VAR_049721"
FT MUTAGEN 40
FT /note="Q->A: 10-fold reduced affinity for EFNB2; when
FT associated with A-42."
FT /evidence="ECO:0000269|PubMed:19875447"
FT MUTAGEN 42
FT /note="E->A: 10-fold reduced affinity for EFNB2; when
FT associated with A-40."
FT /evidence="ECO:0000269|PubMed:19875447"
FT CONFLICT 71
FT /note="Q -> P (in Ref. 2; BAF82995)"
FT /evidence="ECO:0000305"
FT CONFLICT 102
FT /note="K -> R (in Ref. 2; BAF82995)"
FT /evidence="ECO:0000305"
FT CONFLICT 137
FT /note="I -> V (in Ref. 2; BAG35298)"
FT /evidence="ECO:0000305"
FT CONFLICT 362
FT /note="Y -> H (in Ref. 2; BAF82995)"
FT /evidence="ECO:0000305"
FT STRAND 29..35
FT /evidence="ECO:0007829|PDB:7OFV"
FT HELIX 36..38
FT /evidence="ECO:0007829|PDB:7OFV"
FT TURN 40..42
FT /evidence="ECO:0007829|PDB:4M4R"
FT STRAND 46..53
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 55..60
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 62..65
FT /evidence="ECO:0007829|PDB:2LW8"
FT STRAND 66..72
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 77..79
FT /evidence="ECO:0007829|PDB:5JR2"
FT STRAND 82..85
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 93..96
FT /evidence="ECO:0007829|PDB:2LW8"
FT STRAND 97..105
FT /evidence="ECO:0007829|PDB:7OFV"
FT HELIX 108..110
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 114..116
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 119..130
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 131..133
FT /evidence="ECO:0007829|PDB:2LW8"
FT HELIX 139..141
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 142..149
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 154..159
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 162..173
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 178..190
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 192..203
FT /evidence="ECO:0007829|PDB:7OFV"
FT STRAND 207..209
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 212..214
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 226..230
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 237..248
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 257..262
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 266..269
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 272..275
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 304..306
FT /evidence="ECO:0007829|PDB:4M4R"
FT STRAND 333..340
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 343..349
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 361..368
FT /evidence="ECO:0007829|PDB:4M4P"
FT TURN 373..375
FT /evidence="ECO:0007829|PDB:4M4R"
FT STRAND 385..388
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 390..393
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 395..401
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 405..416
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 418..423
FT /evidence="ECO:0007829|PDB:4M4P"
FT HELIX 426..428
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 429..435
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 447..452
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 457..461
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 473..483
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 489..500
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 508..517
FT /evidence="ECO:0007829|PDB:4M4P"
FT STRAND 528..531
FT /evidence="ECO:0007829|PDB:4M4P"
FT TURN 538..540
FT /evidence="ECO:0007829|PDB:4M4P"
SQ SEQUENCE 986 AA; 109860 MW; 0C39C1152EDDD46F CRC64;
MAGIFYFALF SCLFGICDAV TGSRVYPANE VTLLDSRSVQ GELGWIASPL EGGWEEVSIM
DEKNTPIRTY QVCNVMEPSQ NNWLRTDWIT REGAQRVYIE IKFTLRDCNS LPGVMGTCKE
TFNLYYYESD NDKERFIREN QFVKIDTIAA DESFTQVDIG DRIMKLNTEI RDVGPLSKKG
FYLAFQDVGA CIALVSVRVF YKKCPLTVRN LAQFPDTITG ADTSSLVEVR GSCVNNSEEK
DVPKMYCGAD GEWLVPIGNC LCNAGHEERS GECQACKIGY YKALSTDATC AKCPPHSYSV
WEGATSCTCD RGFFRADNDA ASMPCTRPPS APLNLISNVN ETSVNLEWSS PQNTGGRQDI
SYNVVCKKCG AGDPSKCRPC GSGVHYTPQQ NGLKTTKVSI TDLLAHTNYT FEIWAVNGVS
KYNPNPDQSV SVTVTTNQAA PSSIALVQAK EVTRYSVALA WLEPDRPNGV ILEYEVKYYE
KDQNERSYRI VRTAARNTDI KGLNPLTSYV FHVRARTAAG YGDFSEPLEV TTNTVPSRII
GDGANSTVLL VSVSGSVVLV VILIAAFVIS RRRSKYSKAK QEADEEKHLN QGVRTYVDPF
TYEDPNQAVR EFAKEIDASC IKIEKVIGVG EFGEVCSGRL KVPGKREICV AIKTLKAGYT
DKQRRDFLSE ASIMGQFDHP NIIHLEGVVT KCKPVMIITE YMENGSLDAF LRKNDGRFTV
IQLVGMLRGI GSGMKYLSDM SYVHRDLAAR NILVNSNLVC KVSDFGMSRV LEDDPEAAYT
TRGGKIPIRW TAPEAIAYRK FTSASDVWSY GIVMWEVMSY GERPYWDMSN QDVIKAIEEG
YRLPPPMDCP IALHQLMLDC WQKERSDRPK FGQIVNMLDK LIRNPNSLKR TGTESSRPNT
ALLDPSSPEF SAVVSVGDWL QAIKMDRYKD NFTAAGYTTL EAVVHVNQED LARIGITAIT
HQNKILSSVQ AMRTQMQQMH GRMVPV
