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 27-MAR-2024, entry version 225. 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), AND TISSUE SPECIFICITY. 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 Phosphorylates CAPRIN1, promoting CAPRIN1-dependent formation of a CC membraneless compartment (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). 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 P54764; P29323: EPHB2; NbExp=3; IntAct=EBI-5773557, EBI-1059294; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:Q03137}; CC Single-pass type I membrane protein {ECO:0000250|UniProtKB:Q03137}. CC Cell projection, axon {ECO:0000250|UniProtKB:Q03137}. Cell projection, CC dendrite {ECO:0000250|UniProtKB:Q03137}. Postsynaptic density membrane CC {ECO:0000250|UniProtKB:Q03137}. Early endosome CC {ECO:0000250|UniProtKB:Q03137}. Cell junction, adherens junction CC {ECO:0000250|UniProtKB:Q03137}. Note=Clustered upon activation and CC targeted to early endosome. {ECO:0000250|UniProtKB:Q03137}. 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. {ECO:0000269|PubMed:7898931}. CC -!- DOMAIN: The protein kinase domain mediates interaction with NGEF. CC {ECO:0000250|UniProtKB:Q03137}. CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein CC kinase family. Ephrin receptor subfamily. {ECO:0000255|PROSITE- CC ProRule:PRU00159}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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; 178. DR DIP; DIP-48294N; -. DR IntAct; P54764; 160. DR MINT; P54764; -. DR STRING; 9606.ENSP00000281821; -. DR BindingDB; P54764; -. DR ChEMBL; CHEMBL3988; -. DR DrugBank; DB12010; Fostamatinib. DR DrugCentral; P54764; -. DR GuidetoPHARMACOLOGY; 1824; -. DR GlyCosmos; P54764; 4 sites, No reported glycans. DR GlyGen; P54764; 4 sites. DR iPTMnet; P54764; -. DR PhosphoSitePlus; P54764; -. DR BioMuta; EPHA4; -. DR DMDM; 1711371; -. DR CPTAC; CPTAC-2790; -. DR CPTAC; CPTAC-2922; -. DR CPTAC; CPTAC-2923; -. DR EPD; P54764; -. DR jPOST; P54764; -. DR MassIVE; P54764; -. DR MaxQB; P54764; -. DR PaxDb; 9606-ENSP00000281821; -. DR PeptideAtlas; P54764; -. DR ProteomicsDB; 56717; -. [P54764-1] DR Pumba; P54764; -. DR TopDownProteomics; P54764-1; -. [P54764-1] DR ABCD; P54764; 11 sequenced antibodies. DR Antibodypedia; 34350; 802 antibodies from 39 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 AGR; HGNC:3388; -. DR CTD; 2043; -. DR DisGeNET; 2043; -. DR GeneCards; EPHA4; -. DR HGNC; HGNC:3388; EPHA4. DR HPA; ENSG00000116106; Tissue enhanced (brain). 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; DEHNGEC; -. DR OrthoDB; 1614410at2759; -. 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 Reactome; R-HSA-9824272; Somitogenesis. DR SignaLink; P54764; -. DR SIGNOR; P54764; -. DR BioGRID-ORCS; 2043; 17 hits in 1186 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 187 other cell types or tissues. DR ExpressionAtlas; P54764; baseline and differential. 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:0030175; C:filopodium; IEA:Ensembl. DR GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl. DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:Ensembl. DR GO; GO:0031594; C:neuromuscular junction; IEA:Ensembl. DR GO; GO:0043204; C:perikaryon; IEA:Ensembl. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0098839; C:postsynaptic density membrane; IEA:UniProtKB-SubCell. DR GO; GO:0042734; C:presynaptic membrane; IEA:Ensembl. 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:0004713; F:protein tyrosine kinase activity; ISS:UniProt. DR GO; GO:1990782; F:protein tyrosine kinase binding; IPI:ARUK-UCL. 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:0017148; P:negative regulation of translation; ISS:UniProt. 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: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:1905806; P:regulation of synapse pruning; IEA:Ensembl. DR GO; GO:0098883; P:synapse pruning; IEA:Ensembl. DR CDD; cd10482; EphR_LBD_A4; 1. DR CDD; cd00063; FN3; 2. DR CDD; cd05066; PTKc_EphR_A; 1. DR CDD; cd09545; SAM_EPH-A4; 1. DR Gene3D; 2.60.40.1770; ephrin a2 ectodomain; 1. DR Gene3D; 2.60.120.260; Galactose-binding domain-like; 1. DR Gene3D; 2.60.40.10; Immunoglobulins; 2. DR Gene3D; 1.10.150.50; Transcription Factor, Ets-1; 1. DR Gene3D; 1.10.510.10; Transferase(Phosphotransferase) domain 1; 1. DR Gene3D; 2.10.50.10; Tumor Necrosis Factor Receptor, subunit A, domain 2; 1. 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; IPR011641; Tyr-kin_ephrin_A/B_rcpt-like. 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 PANTHER; PTHR46877; EPH RECEPTOR A5; 1. DR PANTHER; PTHR46877:SF18; EPHRIN TYPE-A RECEPTOR 4; 1. DR Pfam; PF14575; EphA2_TM; 1. DR Pfam; PF01404; Ephrin_lbd; 1. DR Pfam; PF07699; Ephrin_rec_like; 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; PR00014; FNTYPEIII. DR PRINTS; PR00109; TYRKINASE. DR SMART; SM00615; EPH_lbd; 1. DR SMART; SM01411; Ephrin_rec_like; 1. DR SMART; SM00060; FN3; 2. DR SMART; SM00220; S_TKc; 1. DR SMART; SM00454; SAM; 1. DR SMART; SM00219; TyrKc; 1. DR SUPFAM; SSF49265; Fibronectin type III; 1. DR SUPFAM; SSF49785; Galactose-binding domain-like; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF47769; SAM/Pointed domain; 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. DR Genevisible; P54764; HS. 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 //