ID EPHA3_MOUSE Reviewed; 983 AA. AC P29319; DT 01-DEC-1992, integrated into UniProtKB/Swiss-Prot. DT 01-DEC-1992, sequence version 1. DT 08-NOV-2023, entry version 191. DE RecName: Full=Ephrin type-A receptor 3; DE EC=2.7.10.1; DE AltName: Full=EPH-like kinase 4; DE Short=EK4; DE Short=mEK4; DE AltName: Full=Tyrosine-protein kinase TYRO4; DE AltName: Full=Tyrosine-protein kinase receptor ETK1; DE Flags: Precursor; GN Name=Epha3; Synonyms=Etk1, Mek4, Tyro4; 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] (ISOFORMS LONG AND SHORT). RC STRAIN=ICR X Swiss Webster; TISSUE=Embryo; RX PubMed=1657122; RA Sajjadi F.G., Pasquale E.B., Subramani S.; RT "Identification of a new eph-related receptor tyrosine kinase gene from RT mouse and chicken that is developmentally regulated and encodes at least RT two forms of the receptor."; RL New Biol. 3:769-778(1991). RN [2] RP INTERACTION WITH CRK. RX PubMed=11870224; DOI=10.1242/jcs.115.5.1059; RA Lawrenson I.D., Wimmer-Kleikamp S.H., Lock P., Schoenwaelder S.M., Down M., RA Boyd A.W., Alewood P.F., Lackmann M.; RT "Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing RT 293T and melanoma cells by CrkII and Rho-mediated signalling."; RL J. Cell Sci. 115:1059-1072(2002). RN [3] RP DISRUPTION PHENOTYPE, AND DEVELOPMENTAL STAGE. RX PubMed=14585969; DOI=10.1128/mcb.23.22.8092-8098.2003; RA Vaidya A., Pniak A., Lemke G., Brown A.; RT "EphA3 null mutants do not demonstrate motor axon guidance defects."; RL Mol. Cell. Biol. 23:8092-8098(2003). RN [4] RP DISRUPTION PHENOTYPE, FUNCTION IN HEART DEVELOPMENT, AND DEVELOPMENTAL RP STAGE. RX PubMed=17046737; DOI=10.1016/j.ydbio.2006.08.058; RA Stephen L.J., Fawkes A.L., Verhoeve A., Lemke G., Brown A.; RT "A critical role for the EphA3 receptor tyrosine kinase in heart RT development."; RL Dev. Biol. 302:66-79(2007). RN [5] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-937, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Mast cell; RX PubMed=17947660; DOI=10.4049/jimmunol.179.9.5864; RA Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y., RA Kawakami T., Salomon A.R.; RT "Quantitative time-resolved phosphoproteomic analysis of mast cell RT signaling."; RL J. Immunol. 179:5864-5876(2007). RN [6] 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 [7] RP FUNCTION IN CELL MIGRATION, AND INTERACTION WITH NCK1. RX PubMed=19505147; DOI=10.1021/bi900831k; RA Hu T., Shi G., Larose L., Rivera G.M., Mayer B.J., Zhou R.; RT "Regulation of process retraction and cell migration by EphA3 is mediated RT by the adaptor protein Nck1."; RL Biochemistry 48:6369-6378(2009). RN [8] 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). CC -!- FUNCTION: Receptor tyrosine kinase which binds promiscuously membrane- CC bound ephrin family ligands residing on adjacent cells, leading to CC contact-dependent bidirectional signaling into neighboring cells. The CC signaling pathway downstream of the receptor is referred to as forward CC signaling while the signaling pathway downstream of the ephrin ligand CC is referred to as reverse signaling. Highly promiscuous for ephrin-A CC ligands it binds preferentially EFNA5. Upon activation by EFNA5 CC regulates cell-cell adhesion, cytoskeletal organization and cell CC migration. Plays a role in cardiac cells migration and differentiation CC and regulates the formation of the atrioventricular canal and septum CC during development probably through activation by EFNA1. Involved in CC the retinotectal mapping of neurons. May also control the segregation CC but not the guidance of motor and sensory axons during neuromuscular CC circuit development. {ECO:0000269|PubMed:17046737, CC ECO:0000269|PubMed:18403711, ECO:0000269|PubMed:19505147}. 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. Forms a ternary CC EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain CC shedding by ADAM10 which regulates the EFNA5-EPHA3 complex CC internalization and function. Interacts (phosphorylated) with PTPN1; CC dephosphorylates EPHA3 and may regulate its trafficking and function CC (By similarity). Interacts (phosphorylated) with CRK; mediates EFNA5- CC EPHA3 signaling through RHOA GTPase activation. Interacts with NCK1 CC (via SH2 domain); mediates EFNA5-EPHA3 signaling. {ECO:0000250, CC ECO:0000269|PubMed:11870224, ECO:0000269|PubMed:19505147}. CC -!- SUBCELLULAR LOCATION: [Isoform Long]: Cell membrane CC {ECO:0000250|UniProtKB:P29320}; Single-pass type I membrane protein CC {ECO:0000255}. CC -!- SUBCELLULAR LOCATION: [Isoform Short]: Secreted CC {ECO:0000250|UniProtKB:P29320}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=Long; CC IsoId=P29319-1; Sequence=Displayed; CC Name=Short; CC IsoId=P29319-3; Sequence=VSP_041882, VSP_041883; CC -!- TISSUE SPECIFICITY: Greatest levels of expression occurring in the CC brain, also detected in testis. Expressed in myogenic progenitor cells CC (PubMed:27446912). {ECO:0000269|PubMed:27446912}. CC -!- DEVELOPMENTAL STAGE: Specifically expressed in heart during its CC development by mesenchymal cells of the endocardial cushions. Expressed CC in motor neurons at 11.5 dpc. In myogenic progenitor cells, highly CC expressed, at least as early as 11.5 dpc, expression decreases until 4 CC weeks after birth (PubMed:27446912). {ECO:0000269|PubMed:14585969, CC ECO:0000269|PubMed:17046737, ECO:0000269|PubMed:27446912}. CC -!- PTM: Autophosphorylates upon activation by EFNA5. Phosphorylation on CC Tyr-602 mediates interaction with NCK1. Dephosphorylated by PTPN1 (By CC similarity). {ECO:0000250}. CC -!- DISRUPTION PHENOTYPE: Mice die perinatally due to cardiac failure. CC {ECO:0000269|PubMed:14585969, ECO:0000269|PubMed:17046737}. 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; M68513; AAA39521.1; -; mRNA. DR EMBL; M68515; AAA39522.1; -; mRNA. DR PIR; A45583; A45583. DR AlphaFoldDB; P29319; -. DR SMR; P29319; -. DR STRING; 10090.ENSMUSP00000066554; -. DR BindingDB; P29319; -. DR ChEMBL; CHEMBL2034794; -. DR GuidetoPHARMACOLOGY; 1823; -. DR GlyCosmos; P29319; 5 sites, No reported glycans. DR GlyGen; P29319; 5 sites. DR iPTMnet; P29319; -. DR PhosphoSitePlus; P29319; -. DR MaxQB; P29319; -. DR PaxDb; 10090-ENSMUSP00000066554; -. DR ProteomicsDB; 275753; -. [P29319-1] DR ProteomicsDB; 275754; -. [P29319-3] DR AGR; MGI:99612; -. DR MGI; MGI:99612; Epha3. DR eggNOG; KOG0196; Eukaryota. DR InParanoid; P29319; -. DR PhylomeDB; P29319; -. 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 ChiTaRS; Epha3; mouse. DR PRO; PR:P29319; -. DR Proteomes; UP000000589; Unplaced. DR RNAct; P29319; Protein. DR GO; GO:0015629; C:actin cytoskeleton; ISO:MGI. DR GO; GO:0005829; C:cytosol; ISO:MGI. DR GO; GO:0030425; C:dendrite; IBA:GO_Central. DR GO; GO:0005769; C:early endosome; ISS:UniProtKB. DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell. DR GO; GO:0098982; C:GABA-ergic synapse; IDA:SynGO. DR GO; GO:0031965; C:nuclear membrane; ISO:MGI. DR GO; GO:0005654; C:nucleoplasm; ISO:MGI. DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB. DR GO; GO:0098793; C:presynapse; IDA:SynGO. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0005003; F:ephrin receptor activity; IDA:MGI. DR GO; GO:0005004; F:GPI-linked ephrin receptor activity; ISS:UniProtKB. DR GO; GO:0019838; F:growth factor binding; IPI:ARUK-UCL. DR GO; GO:0005005; F:transmembrane-ephrin receptor activity; IBA:GO_Central. DR GO; GO:0007411; P:axon guidance; IBA:GO_Central. DR GO; GO:0016477; P:cell migration; IMP:UniProtKB. DR GO; GO:0071372; P:cellular response to follicle-stimulating hormone stimulus; IDA:MGI. DR GO; GO:0071300; P:cellular response to retinoic acid; ISO:MGI. DR GO; GO:0003197; P:endocardial cushion development; IMP:UniProtKB. DR GO; GO:0048013; P:ephrin receptor signaling pathway; IDA:UniProtKB. 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:0045806; P:negative regulation of endocytosis; ISO:MGI. DR GO; GO:0010977; P:negative regulation of neuron projection development; IDA:MGI. DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW. DR GO; GO:0010976; P:positive regulation of neuron projection development; ISO:MGI. DR GO; GO:1903078; P:positive regulation of protein localization to plasma membrane; ISO:MGI. DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; ISS:UniProtKB. DR GO; GO:0030334; P:regulation of cell migration; IGI:MGI. DR GO; GO:0010717; P:regulation of epithelial to mesenchymal transition; IMP:UniProtKB. DR GO; GO:0051893; P:regulation of focal adhesion assembly; ISS:UniProtKB. DR GO; GO:0043087; P:regulation of GTPase activity; ISS:UniProtKB. DR GO; GO:0070507; P:regulation of microtubule cytoskeleton organization; ISS:UniProtKB. DR GO; GO:0099560; P:synaptic membrane adhesion; IDA:SynGO. DR CDD; cd10481; EphR_LBD_A3; 1. DR CDD; cd00063; FN3; 2. DR CDD; cd05066; PTKc_EphR_A; 1. DR CDD; cd09544; SAM_EPH-A3; 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; IPR034266; EphA3_rcpt_lig-bd. DR InterPro; IPR001090; Ephrin_rcpt_lig-bd_dom. DR InterPro; IPR003961; FN3_dom. DR InterPro; IPR036116; FN3_sf. DR InterPro; IPR008979; Galactose-bd-like_sf. DR InterPro; IPR009030; Growth_fac_rcpt_cys_sf. DR InterPro; IPR013783; Ig-like_fold. DR InterPro; IPR011009; Kinase-like_dom_sf. DR InterPro; IPR000719; Prot_kinase_dom. DR InterPro; IPR017441; Protein_kinase_ATP_BS. DR InterPro; IPR001660; SAM. DR InterPro; IPR013761; SAM/pointed_sf. DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom. DR InterPro; 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:SF12; EPHRIN TYPE-A RECEPTOR 3; 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; 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; SSF57184; Growth factor receptor domain; 1. DR SUPFAM; SSF56112; Protein kinase-like (PK-like); 1. DR SUPFAM; SSF47769; SAM/Pointed domain; 1. DR PROSITE; PS01186; EGF_2; 1. DR PROSITE; PS51550; EPH_LBD; 1. DR PROSITE; PS50853; FN3; 2. DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1. DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1. DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1. DR PROSITE; 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 Alternative splicing; ATP-binding; Cell membrane; Glycoprotein; Kinase; KW Membrane; Nucleotide-binding; Phosphoprotein; Receptor; Reference proteome; KW Repeat; Secreted; Signal; Transferase; Transmembrane; Transmembrane helix; KW Tyrosine-protein kinase. FT SIGNAL 1..20 FT /evidence="ECO:0000250" FT CHAIN 21..983 FT /note="Ephrin type-A receptor 3" FT /id="PRO_0000016803" FT TOPO_DOM 21..540 FT /note="Extracellular" FT /evidence="ECO:0000255" FT TRANSMEM 541..564 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 565..983 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 29..206 FT /note="Eph LBD" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00883" FT DOMAIN 324..434 FT /note="Fibronectin type-III 1" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316" FT DOMAIN 435..530 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 981..983 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 628..633 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 BINDING 700..706 FT /ligand="ATP" FT /ligand_id="ChEBI:CHEBI:30616" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159" FT BINDING 750..751 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:P29320" FT MOD_RES 602 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P29320" FT MOD_RES 701 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P29320" FT MOD_RES 779 FT /note="Phosphotyrosine; by autocatalysis" FT /evidence="ECO:0000250|UniProtKB:P29320" FT MOD_RES 937 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:17947660" FT CARBOHYD 231 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 336 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 390 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 403 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 492 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT VAR_SEQ 531..537 FT /note="SFSISGE -> CMYYFSF (in isoform Short)" FT /evidence="ECO:0000303|PubMed:1657122" FT /id="VSP_041882" FT VAR_SEQ 538..983 FT /note="Missing (in isoform Short)" FT /evidence="ECO:0000303|PubMed:1657122" FT /id="VSP_041883" SQ SEQUENCE 983 AA; 109955 MW; BE44A6655D8107A2 CRC64; MDCHLSILVL LGCCVLSCSG ELSPQPSNEV NLLDSKTIQG ELGWISYPSH GWEEISGVDE HYTPIRTYQV CNVMDHSQNN WLRTNWVPRN SAQKIYVELK FTLRDCNSIP LVLGTCKETF NLYYMESDDH GVKFREHQFT KIDTIAADES FTQMDLGDRI LKLNTEIREV GPVNKKGFYL AFQDVGACVA LVSVRVYFKK CPFTVKNLAM FPDTVPMDSQ SLVEVRGSCV NNSKEEDPPR MYCSTEGEWL VPIGKCTCNA GYEERGFICQ ACRPGFYKAS DGAAKCAKCP PHSSTQEDGS MNCRCENNYF RAEKDPPSMA CARPPSAPRN VISNINETSV ILDWSWPLDT GGRKDITFNI ICKKCGWNVR QCEPCSPNVR FLPRQLGLTN TTVTVTDLLA HTNYTFEIDA VNGVSELSSP PRQYAAVSIT TNQAAPSPVM TIKKDRTSRN SISLSWQEPE HPNGIILDYE VKYYQKQEQE TSYTILRARG TNVTISSLKP DTTYVFQIRA RTAAGYGTNS RKFEFETSPD SFSISGENSH VVMIAISAAV AIIVLTVVTY VLVGRFCGYH KSKHSAEEKR LHFGNGHLKL PGLRTYVDPH TYEDPTQAVH EFAKELDATN ISIDKVVGAG EFGEVCSGRL KLPSKKEISV AIKTLKVGYT EKQRRDFLGE ASIMGQFDHP NIIRLEGVVT KSKPEMIVTE YMENGSLDSF LRKHDAQFTV IQLVGMLRGI ASGMKYLSDM GYVHRDLAAR NILINSNLVC KVSDFGLSRV LEDDPEAAYT TRGGKIPIRW TSPEAMSYRK FTSASDVWSY GIVLWEVMSY GERPYSQMSN QDVIKAVDER YRLPPPMDCP AALYQLMLDC WQKDRNNRPK FEQIVSILDK LIRNPGSLKI ITSAAARPSN LLLDQSNVDI ATFHTTGDWL NGMRTAHCKE IFTGVEYSSC DTIAKISTDD MKKVGVTVVG PQKKIISTIK ALETQSKNGP VPV //