ID EPHA4_MOUSE Reviewed; 986 AA. AC Q03137; Q80VZ2; DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot. DT 27-JUL-2011, sequence version 2. DT 27-MAR-2024, entry version 230. DE RecName: Full=Ephrin type-A receptor 4; DE EC=2.7.10.1 {ECO:0000269|PubMed:31439799}; DE AltName: Full=Tyrosine-protein kinase receptor MPK-3; DE AltName: Full=Tyrosine-protein kinase receptor SEK-1; DE Flags: Precursor; GN Name=Epha4; Synonyms=Sek, Sek1; OS Mus musculus (Mouse). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Mus; Mus. OX NCBI_TaxID=10090; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM LONG). RC STRAIN=C57BL/6J; TISSUE=Embryonic brain; RX PubMed=1281307; RA Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G., Chestier A., RA Wilkinson D.G., Charnay P.; RT "An Eph-related receptor protein tyrosine kinase gene segmentally expressed RT in the developing mouse hindbrain."; RL Oncogene 7:2499-2506(1992). RN [2] RP ERRATUM OF PUBMED:1281307. RX PubMed=8455939; RA Gilardi-Hebenstreit P., Nieto M.A., Frain M., Mattei M.-G., Chestier A., RA Wilkinson D.G., Charnay P.; RL Oncogene 8:1103-1103(1993). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG). RC STRAIN=C57BL/6J; RX PubMed=16141072; DOI=10.1126/science.1112014; RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J., RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.; RT "The transcriptional landscape of the mammalian genome."; RL Science 309:1559-1563(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM LONG). RC TISSUE=Limb; 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 [6] RP PHOSPHORYLATION AT TYR-596 AND TYR-602, AND INTERACTION WITH FYN. RX PubMed=8622893; RA Ellis C., Kasmi F., Ganju P., Walls E., Panayotou G., Reith A.D.; RT "A juxtamembrane autophosphorylation site in the Eph family receptor RT tyrosine kinase, Sek, mediates high affinity interaction with p59fyn."; RL Oncogene 12:1727-1736(1996). RN [7] RP DISRUPTION PHENOTYPE, AND FUNCTION IN AXON GUIDANCE. RX PubMed=9789074; DOI=10.1073/pnas.95.22.13248; RA Dottori M., Hartley L., Galea M., Paxinos G., Polizzotto M., Kilpatrick T., RA Bartlett P.F., Murphy M., Koentgen F., Boyd A.W.; RT "EphA4 (Sek1) receptor tyrosine kinase is required for the development of RT the corticospinal tract."; RL Proc. Natl. Acad. Sci. U.S.A. 95:13248-13253(1998). RN [8] RP INTERACTION WITH NGEF, AND MUTAGENESIS OF VAL-635. RX PubMed=11336673; DOI=10.1016/s0092-8674(01)00314-2; RA Shamah S.M., Lin M.Z., Goldberg J.L., Estrach S., Sahin M., Hu L., RA Bazalakova M., Neve R.L., Corfas G., Debant A., Greenberg M.E.; RT "EphA receptors regulate growth cone dynamics through the novel guanine RT nucleotide exchange factor ephexin."; RL Cell 105:233-244(2001). RN [9] RP DEVELOPMENTAL STAGE. RX PubMed=14516691; DOI=10.1016/s0925-4773(03)00122-9; RA Greferath U., Canty A.J., Messenger J., Murphy M.; RT "Developmental expression of EphA4-tyrosine kinase receptor in the mouse RT brain and spinal cord."; RL Mech. Dev. 119:S231-S238(2002). RN [10] RP DISRUPTION PHENOTYPE, AND FUNCTION IN AXONAL REGENERATION. RX PubMed=15537875; DOI=10.1523/jneurosci.2981-04.2004; RA Goldshmit Y., Galea M.P., Wise G., Bartlett P.F., Turnley A.M.; RT "Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient RT mice."; RL J. Neurosci. 24:10064-10073(2004). RN [11] RP FUNCTION IN ANGIOGENESIS. RX PubMed=16802330; DOI=10.1002/cne.21029; RA Goldshmit Y., Galea M.P., Bartlett P.F., Turnley A.M.; RT "EphA4 regulates central nervous system vascular formation."; RL J. Comp. Neurol. 497:864-875(2006). RN [12] RP DISRUPTION PHENOTYPE, AND FUNCTION IN THYMUS DEVELOPMENT. RX PubMed=16818734; DOI=10.4049/jimmunol.177.2.804; RA Munoz J.J., Alfaro D., Garcia-Ceca J., Alonso-C L.M., Jimenez E., RA Zapata A.; RT "Thymic alterations in EphA4-deficient mice."; RL J. Immunol. 177:804-813(2006). RN [13] RP FUNCTION IN RAC1 REGULATION, FUNCTION IN AXON GUIDANCE, AND INTERACTION RP WITH CHN1. RX PubMed=17719550; DOI=10.1016/j.cell.2007.07.022; RA Iwasato T., Katoh H., Nishimaru H., Ishikawa Y., Inoue H., Saito Y.M., RA Ando R., Iwama M., Takahashi R., Negishi M., Itohara S.; RT "Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator RT of EphrinB3/EphA4 forward signaling."; RL Cell 130:742-753(2007). RN [14] RP FUNCTION IN NEURON MORPHOLOGY, AND 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 [15] RP FUNCTION IN DENDRITIC SPINE MORPHOGENESIS, TOPOLOGY, SUBCELLULAR LOCATION, RP AND INTERACTION WITH NGEF. 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 [16] RP FUNCTION IN AXON GUIDANCE, INTERACTION WITH CHN1, AND MUTAGENESIS OF RP VAL-635. RX PubMed=17785183; DOI=10.1016/j.neuron.2007.07.036; RA Beg A.A., Sommer J.E., Martin J.H., Scheiffele P.; RT "alpha2-Chimaerin is an essential EphA4 effector in the assembly of RT neuronal locomotor circuits."; RL Neuron 55:768-778(2007). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-602, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain; RX PubMed=18034455; DOI=10.1021/pr0701254; RA Ballif B.A., Carey G.R., Sunyaev S.R., Gygi S.P.; RT "Large-scale identification and evolution indexing of tyrosine RT phosphorylation sites from murine brain."; RL J. Proteome Res. 7:311-318(2008). RN [18] RP FUNCTION IN MOTOR AND SENSORY AXONS SEGREGATION. RX PubMed=18403711; DOI=10.1126/science.1153758; RA Gallarda B.W., Bonanomi D., Mueller D., Brown A., Alaynick W.A., RA Andrews S.E., Lemke G., Pfaff S.L., Marquardt T.; RT "Segregation of axial motor and sensory pathways via heterotypic trans- RT axonal signaling."; RL Science 320:233-236(2008). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Brain, and Heart; RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001; RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R., RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.; RT "A tissue-specific atlas of mouse protein phosphorylation and expression."; RL Cell 143:1174-1189(2010). RN [20] RP DEVELOPMENTAL STAGE, AND TISSUE SPECIFICITY. RX PubMed=27446912; DOI=10.3389/fcell.2016.00058; RA Alonso-Martin S., Rochat A., Mademtzoglou D., Morais J., de Reynies A., RA Aurade F., Chang T.H., Zammit P.S., Relaix F.; RT "Gene expression profiling of muscle stem cells identifies novel regulators RT of postnatal myogenesis."; RL Front. Cell Dev. Biol. 4:58-58(2016). RN [21] RP FUNCTION, IDENTIFICATION IN COMPLEX WITH ADAM10 AND CADH1, SUBCELLULAR RP LOCATION, AND TISSUE SPECIFICITY. RX PubMed=30639848; DOI=10.1016/j.isci.2018.12.017; RA Defourny J., Peuckert C., Kullander K., Malgrange B.; RT "EphA4-ADAM10 Interplay Patterns the Cochlear Sensory Epithelium through RT Local Disruption of Adherens Junctions."; RL IScience 11:246-257(2019). RN [22] RP FUNCTION, AND CATALYTIC ACTIVITY. RX PubMed=31439799; DOI=10.1126/science.aax4240; RA Kim T.H., Tsang B., Vernon R.M., Sonenberg N., Kay L.E., Forman-Kay J.D.; RT "Phospho-dependent phase separation of FMRP and CAPRIN1 recapitulates RT regulation of translation and deadenylation."; RL Science 365:825-829(2019). 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 (PubMed:17719550). Plays an important role in CC the development of the nervous system controlling different steps of CC axonal guidance including the establishment of the corticospinal CC projections (PubMed:9789074, PubMed:17719550, PubMed:17785183). May CC also control the segregation of motor and sensory axons during CC neuromuscular circuit developmen (PubMed:18403711). In addition to its CC role in axonal guidance plays a role in synaptic plasticity. Activated CC by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates CC NGEF regulating RHOA and dendritic spine morphogenesis CC (PubMed:17143272). In the nervous system, also plays a role in repair CC after injury preventing axonal regeneration and in angiogenesis playing CC a role in central nervous system vascular formation (PubMed:15537875, CC PubMed:16802330). 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 (PubMed:16818734). During CC development of the cochlear organ of Corti, regulates pillar cell CC separation by forming a ternary complex with ADAM10 and CADH1 which CC facilitates the cleavage of CADH1 by ADAM10 and disruption of adherens CC junctions (PubMed:30639848). Phosphorylates CAPRIN1, promoting CAPRIN1- CC dependent formation of a membraneless compartment (PubMed:31439799). CC {ECO:0000269|PubMed:15537875, ECO:0000269|PubMed:16802330, CC ECO:0000269|PubMed:16818734, ECO:0000269|PubMed:17143272, CC ECO:0000269|PubMed:17719550, ECO:0000269|PubMed:17785183, CC ECO:0000269|PubMed:18094260, ECO:0000269|PubMed:18403711, CC ECO:0000269|PubMed:30639848, ECO:0000269|PubMed:31439799, CC ECO:0000269|PubMed:9789074}. 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 ECO:0000269|PubMed:31439799}; 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 (via PDZ CC motif) with SIPA1L1 (via PDZ domain); controls neuronal morphology CC through regulation of the RAP1 (RAP1A or RAP1B) and RAP2 (RAP2A, RAP2B CC or RAP2C) GTPases. Interacts with CDK5, CDK5R1 and NGEF; upon CC activation by EFNA1 induces NGEF phosphorylation by the kinase CDK5. CC Interacts with CHN1; effector of EPHA4 in axon guidance linking EPHA4 CC activation to RAC1 regulation. Forms a ternary complex composed of CC ADAM10, CADH1 and EPHA4; within the complex, CADH1 is cleaved by ADAM10 CC which disrupts adherens junctions (PubMed:30639848). CC {ECO:0000269|PubMed:11336673, ECO:0000269|PubMed:17143272, CC ECO:0000269|PubMed:17719550, ECO:0000269|PubMed:17785183, CC ECO:0000269|PubMed:18094260, ECO:0000269|PubMed:30639848, CC ECO:0000269|PubMed:8622893}. CC -!- INTERACTION: CC Q03137; Q91V57-1: Chn1; NbExp=2; IntAct=EBI-1539152, EBI-1539203; CC Q03137; P52800: Efnb2; NbExp=2; IntAct=EBI-1539152, EBI-1032676; CC Q03137; Q03145: Epha2; NbExp=3; IntAct=EBI-1539152, EBI-529701; CC Q03137; Q03137: Epha4; NbExp=2; IntAct=EBI-1539152, EBI-1539152; CC Q03137; P54763: Ephb2; NbExp=3; IntAct=EBI-1539152, EBI-537711; CC Q03137; Q921Q7: Rin1; NbExp=2; IntAct=EBI-1539152, EBI-15724937; CC Q03137; O95292: VAPB; Xeno; NbExp=2; IntAct=EBI-1539152, EBI-1188298; CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000269|PubMed:17143272}; CC Single-pass type I membrane protein {ECO:0000269|PubMed:17143272}. Cell CC projection, axon {ECO:0000269|PubMed:17143272}. Cell projection, CC dendrite {ECO:0000269|PubMed:17143272}. Postsynaptic density membrane CC {ECO:0000250}. Early endosome {ECO:0000269|PubMed:17143272}. Cell CC junction, adherens junction {ECO:0000269|PubMed:30639848}. CC Note=Clustered upon activation and targeted to early endosome. CC {ECO:0000269|PubMed:17143272}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Long; CC IsoId=Q03137-1; Sequence=Displayed; CC Name=Short; CC IsoId=Q03137-2; Sequence=VSP_002998; CC -!- TISSUE SPECIFICITY: Expressed in inner and outer pillar cells of the CC organ of Corti (at protein level) (PubMed:30639848). Highest expression CC in the adult brain and retina and also detectable in kidney, lung, CC skeletal muscle and thymus. Not detected in heart and liver. Expressed CC in myogenic progenitor cells (PubMed:27446912). CC {ECO:0000269|PubMed:27446912, ECO:0000269|PubMed:30639848}. CC -!- DEVELOPMENTAL STAGE: Found in both the 10-day embryonic brain and body CC tissues. In the embryonic brain, expressed in the developing cortex of CC the telencephalon and major cortical tracts. Also expressed in the CC hippocampus, fornix and striatal cells and tracts. In the diencephalon, CC strongly expressed in thalamus, hypothalamus and thalamo-cortical CC projection. Also expressed in red nuclei of the mesencephalon and in CC the cerebellum. In the spinal cord, persistent expression occurs in the CC dorsal funiculus and ventral gray matter. In myogenic progenitor cells, CC highly expressed at 11.5 dpc and ceases its expression at the late CC fetal stage (17.5 dpc) (PubMed:27446912). {ECO:0000269|PubMed:14516691, CC ECO:0000269|PubMed:27446912}. CC -!- DOMAIN: The protein kinase domain mediates interaction with NGEF. CC -!- DISRUPTION PHENOTYPE: Mice are viable and fertile but display a loss of CC coordination of limb movement associated with disruptions of cortico- CC spinal tract. They also display altered development of the thymic CC epithelium which leads to a defective T-cells development. CC {ECO:0000269|PubMed:15537875, ECO:0000269|PubMed:16818734, CC ECO:0000269|PubMed:9789074}. 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; X65138; CAA46268.1; -; mRNA. DR EMBL; X57241; CAA40517.1; -; mRNA. DR EMBL; S57168; AAB25836.1; -; mRNA. DR EMBL; AK147698; BAE28081.1; -; mRNA. DR EMBL; CH466548; EDL00429.1; -; Genomic_DNA. DR EMBL; BC052164; AAH52164.1; -; mRNA. DR CCDS; CCDS35627.1; -. [Q03137-1] DR PIR; S78059; S78059. DR RefSeq; NP_031962.2; NM_007936.3. [Q03137-1] DR PDB; 1B0X; X-ray; 2.00 A; A=890-981. DR PDB; 2HEL; X-ray; 2.35 A; A=591-896. DR PDB; 2XYU; X-ray; 2.12 A; A=612-896. DR PDB; 2Y6M; X-ray; 1.70 A; A=606-896. DR PDB; 2Y6O; X-ray; 1.54 A; A=606-896. DR PDBsum; 1B0X; -. DR PDBsum; 2HEL; -. DR PDBsum; 2XYU; -. DR PDBsum; 2Y6M; -. DR PDBsum; 2Y6O; -. DR AlphaFoldDB; Q03137; -. DR SMR; Q03137; -. DR BioGRID; 199471; 6. DR DIP; DIP-1019N; -. DR IntAct; Q03137; 12. DR MINT; Q03137; -. DR STRING; 10090.ENSMUSP00000027451; -. DR BindingDB; Q03137; -. DR ChEMBL; CHEMBL1293259; -. DR GuidetoPHARMACOLOGY; 1824; -. DR GlyConnect; 2295; 1 N-Linked glycan (1 site). DR GlyCosmos; Q03137; 3 sites, 1 glycan. DR GlyGen; Q03137; 4 sites, 1 N-linked glycan (1 site), 1 O-linked glycan (1 site). DR iPTMnet; Q03137; -. DR PhosphoSitePlus; Q03137; -. DR SwissPalm; Q03137; -. DR MaxQB; Q03137; -. DR PaxDb; 10090-ENSMUSP00000027451; -. DR PeptideAtlas; Q03137; -. DR ProteomicsDB; 275755; -. [Q03137-1] DR ProteomicsDB; 275756; -. [Q03137-2] DR Pumba; Q03137; -. DR Antibodypedia; 34350; 802 antibodies from 39 providers. DR DNASU; 13838; -. DR Ensembl; ENSMUST00000027451.13; ENSMUSP00000027451.7; ENSMUSG00000026235.15. [Q03137-1] DR Ensembl; ENSMUST00000188797.7; ENSMUSP00000140954.2; ENSMUSG00000026235.15. [Q03137-1] DR Ensembl; ENSMUST00000188952.7; ENSMUSP00000139640.2; ENSMUSG00000026235.15. [Q03137-1] DR GeneID; 13838; -. DR KEGG; mmu:13838; -. DR UCSC; uc007bpz.1; mouse. [Q03137-1] DR AGR; MGI:98277; -. DR CTD; 2043; -. DR MGI; MGI:98277; Epha4. DR VEuPathDB; HostDB:ENSMUSG00000026235; -. DR eggNOG; KOG0196; Eukaryota. DR GeneTree; ENSGT00940000156948; -. DR HOGENOM; CLU_000288_141_4_1; -. DR InParanoid; Q03137; -. DR OMA; DEHNGEC; -. DR OrthoDB; 1614410at2759; -. DR PhylomeDB; Q03137; -. DR TreeFam; TF315608; -. DR BRENDA; 2.7.10.1; 3474. DR Reactome; R-MMU-2682334; EPH-Ephrin signaling. DR Reactome; R-MMU-3928663; EPHA-mediated growth cone collapse. DR Reactome; R-MMU-3928665; EPH-ephrin mediated repulsion of cells. DR BioGRID-ORCS; 13838; 1 hit in 80 CRISPR screens. DR ChiTaRS; Epha4; mouse. DR EvolutionaryTrace; Q03137; -. DR PRO; PR:Q03137; -. DR Proteomes; UP000000589; Chromosome 1. DR RNAct; Q03137; Protein. DR Bgee; ENSMUSG00000026235; Expressed in rostral migratory stream and 294 other cell types or tissues. DR ExpressionAtlas; Q03137; baseline and differential. DR GO; GO:0005912; C:adherens junction; IEA:UniProtKB-SubCell. DR GO; GO:0030424; C:axon; IDA:UniProtKB. DR GO; GO:0043679; C:axon terminus; ISO:MGI. DR GO; GO:0044295; C:axonal growth cone; ISO:MGI. DR GO; GO:0044297; C:cell body; ISO:MGI. DR GO; GO:0042995; C:cell projection; ISO:MGI. DR GO; GO:0009986; C:cell surface; ISO:MGI. DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB. DR GO; GO:0030425; C:dendrite; IDA:UniProtKB. DR GO; GO:0043198; C:dendritic shaft; ISO:MGI. DR GO; GO:0043197; C:dendritic spine; ISO:MGI. DR GO; GO:0031901; C:early endosome membrane; IDA:UniProtKB. DR GO; GO:0030175; C:filopodium; ISO:MGI. DR GO; GO:0098978; C:glutamatergic synapse; IDA:SynGO. DR GO; GO:0005741; C:mitochondrial outer membrane; ISO:MGI. DR GO; GO:0031594; C:neuromuscular junction; ISO:MGI. DR GO; GO:0043204; C:perikaryon; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB. DR GO; GO:0014069; C:postsynaptic density; ISO:MGI. DR GO; GO:0098839; C:postsynaptic density membrane; IEA:UniProtKB-SubCell. DR GO; GO:0045211; C:postsynaptic membrane; IDA:SynGO. DR GO; GO:0042734; C:presynaptic membrane; IDA:SynGO. DR GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IDA:SynGO. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0097161; F:DH domain binding; ISS:UniProtKB. DR GO; GO:0046875; F:ephrin receptor binding; ISO:MGI. DR GO; GO:0005004; F:GPI-linked ephrin receptor activity; IMP:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0016301; F:kinase activity; ISO:MGI. DR GO; GO:0042731; F:PH domain binding; ISO:MGI. DR GO; GO:0004672; F:protein kinase activity; ISS:UniProtKB. DR GO; GO:1990782; F:protein tyrosine kinase binding; ISO:MGI. DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IDA:UniProtKB. DR GO; GO:0005005; F:transmembrane-ephrin receptor activity; IDA:UniProtKB. DR GO; GO:0034332; P:adherens junction organization; IMP:ARUK-UCL. DR GO; GO:0007628; P:adult walking behavior; IMP:MGI. DR GO; GO:0007411; P:axon guidance; IMP:MGI. DR GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW. DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL. DR GO; GO:0090102; P:cochlea development; IMP:UniProtKB. DR GO; GO:0021957; P:corticospinal tract morphogenesis; IMP:UniProtKB. DR GO; GO:0048013; P:ephrin receptor signaling pathway; ISO:MGI. DR GO; GO:0097156; P:fasciculation of motor neuron axon; IMP:UniProtKB. DR GO; GO:0097155; P:fasciculation of sensory neuron axon; IMP:UniProtKB. DR GO; GO:0008347; P:glial cell migration; ISO:MGI. DR GO; GO:0008045; P:motor neuron axon guidance; IMP:UniProtKB. DR GO; GO:0048681; P:negative regulation of axon regeneration; IMP:UniProtKB. DR GO; GO:0007162; P:negative regulation of cell adhesion; ISO:MGI. DR GO; GO:0030336; P:negative regulation of cell migration; ISO:MGI. DR GO; GO:1900038; P:negative regulation of cellular response to hypoxia; ISO:MGI. DR GO; GO:0010719; P:negative regulation of epithelial to mesenchymal transition; ISO:MGI. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISO:MGI. DR GO; GO:1900272; P:negative regulation of long-term synaptic potentiation; IGI:ARUK-UCL. DR GO; GO:0010977; P:negative regulation of neuron projection development; IDA:ARUK-UCL. DR GO; GO:1903051; P:negative regulation of proteolysis involved in protein catabolic process; ISO:MGI. DR GO; GO:0072178; P:nephric duct morphogenesis; IGI:MGI. DR GO; GO:0106030; P:neuron projection fasciculation; IDA:ARUK-UCL. DR GO; GO:0097485; P:neuron projection guidance; IDA:ARUK-UCL. DR GO; GO:0018108; P:peptidyl-tyrosine phosphorylation; ISS:UniProtKB. DR GO; GO:1902004; P:positive regulation of amyloid-beta formation; ISO:MGI. DR GO; GO:0045785; P:positive regulation of cell adhesion; ISO:MGI. DR GO; GO:0030335; P:positive regulation of cell migration; ISO:MGI. DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISO:MGI. DR GO; GO:0050775; P:positive regulation of dendrite morphogenesis; ISO:MGI. DR GO; GO:0043507; P:positive regulation of JUN kinase activity; IDA:BHF-UCL. DR GO; GO:0061098; P:positive regulation of protein tyrosine kinase activity; IGI:ARUK-UCL. DR GO; GO:2001108; P:positive regulation of Rho guanyl-nucleotide exchange factor activity; ISS:UniProtKB. DR GO; GO:0046777; P:protein autophosphorylation; ISS:UniProtKB. DR GO; GO:0050821; P:protein stabilization; ISO:MGI. DR GO; GO:0048710; P:regulation of astrocyte differentiation; IMP:UniProtKB. DR GO; GO:0050770; P:regulation of axonogenesis; IMP:UniProtKB. DR GO; GO:0061001; P:regulation of dendritic spine morphogenesis; IMP:UniProtKB. DR GO; GO:0043087; P:regulation of GTPase activity; IDA:UniProtKB. DR GO; GO:1905244; P:regulation of modification of synaptic structure; IGI:ARUK-UCL. DR GO; GO:1905806; P:regulation of synapse pruning; ISO:MGI. DR GO; GO:0098883; P:synapse pruning; IDA:SynGO. 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; Q03137; MM. 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_0000016808" 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:0000269|PubMed:8622893" FT MOD_RES 602 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000269|PubMed:8622893, FT ECO:0007744|PubMed:18034455" 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 VAR_SEQ 783..832 FT /note="Missing (in isoform Short)" FT /evidence="ECO:0000305" FT /id="VSP_002998" FT MUTAGEN 635 FT /note="V->M: Kinase dead; loss of autophosphorylation and FT loss of CHN1 phosphorylation. No effect on interaction with FT NGEF." FT /evidence="ECO:0000269|PubMed:11336673, FT ECO:0000269|PubMed:17785183" FT CONFLICT 145 FT /note="I -> T (in Ref. 1; CAA46268/AAB25836)" FT /evidence="ECO:0000305" FT HELIX 618..620 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 621..629 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 631..640 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 648..655 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 661..674 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 685..689 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 691..694 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 696..700 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 707..712 FT /evidence="ECO:0007829|PDB:2Y6O" FT TURN 713..716 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 720..739 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 749..751 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 752..754 FT /evidence="ECO:0007829|PDB:2Y6O" FT STRAND 760..762 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 788..790 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 793..798 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 803..818 FT /evidence="ECO:0007829|PDB:2Y6O" FT TURN 824..827 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 830..838 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 851..860 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 865..867 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 871..883 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 885..888 FT /evidence="ECO:0007829|PDB:2Y6O" FT HELIX 916..922 FT /evidence="ECO:0007829|PDB:1B0X" FT HELIX 926..928 FT /evidence="ECO:0007829|PDB:1B0X" FT HELIX 929..934 FT /evidence="ECO:0007829|PDB:1B0X" FT HELIX 940..943 FT /evidence="ECO:0007829|PDB:1B0X" FT HELIX 948..954 FT /evidence="ECO:0007829|PDB:1B0X" FT HELIX 959..977 FT /evidence="ECO:0007829|PDB:1B0X" FT HELIX 978..980 FT /evidence="ECO:0007829|PDB:1B0X" SQ SEQUENCE 986 AA; 109814 MW; 89BEB2C7CDB54A55 CRC64; MAGIFYFILF SFLFGICDAV TGSRVYPANE VTLLDSRSVQ GELGWIASPL EGGWEEVSIM DEKNTPIRTY QVCNVMEASQ NNWLRTDWIT REGAQRVYIE IKFTLRDCNS LPGVMGTCKE TFNLYYYESD NDKERFIRES QFGKIDTIAA DESFTQVDIG DRIMKLNTEI RDVGPLSKKG FYLAFQDVGA CIALVSVRVF YKKCPLTVRN LAQFPDTITG ADTSSLVEVR GSCVNNSEEK DVPKMYCGAD GEWLVPIGNC LCNAGHEEQN GECQACKIGY YKALSTDASC AKCPPHSYSV WEGATSCTCD RGFFRADNDA ASMPCTRPPS APLNLISNVN ETSVNLEWSS PQNTGGRQDI SYNVVCKKCG AGDPSKCRPC GSGVHYTPQQ NGLKTTRVSI TDLLAHTNYT FEIWAVNGVS KYNPSPDQSV 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 TGSESSRPNT ALLDPSSPEF SAVVSVGDWL QAIKMDRYKD NFTAAGYTTL EAVVHMSQDD LARIGITAIT HQNKILSSVQ AMRTQMQQMH GRMVPV //