EPHA5_MOUSE
ID EPHA5_MOUSE Reviewed; 876 AA.
AC Q60629; E9QPV2;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 19-OCT-2011, sequence version 2.
DT 03-AUG-2022, entry version 199.
DE RecName: Full=Ephrin type-A receptor 5;
DE EC=2.7.10.1;
DE AltName: Full=Brain-specific kinase;
DE AltName: Full=CEK-7;
DE AltName: Full=EPH homology kinase 1;
DE Short=EHK-1;
DE Flags: Precursor;
GN Name=Epha5; Synonyms=Bsk {ECO:0000303|PubMed:8145300}, Ehk1;
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], TISSUE SPECIFICITY, AND DEVELOPMENTAL STAGE.
RC STRAIN=BALB/cJ; TISSUE=Brain;
RX PubMed=8145300; DOI=10.1002/jnr.490370117;
RA Zhou R., Copeland T.D., Kromer L.F., Schulz N.T.;
RT "Isolation and characterization of Bsk, a growth factor receptor-like
RT tyrosine kinase associated with the limbic system.";
RL J. Neurosci. Res. 37:129-143(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=C57BL/6J;
RX PubMed=19468303; DOI=10.1371/journal.pbio.1000112;
RA Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X.,
RA Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y.,
RA Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S.,
RA Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R.,
RA Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K.,
RA Eichler E.E., Ponting C.P.;
RT "Lineage-specific biology revealed by a finished genome assembly of the
RT mouse.";
RL PLoS Biol. 7:E1000112-E1000112(2009).
RN [3]
RP FUNCTION IN AXON GUIDANCE, AND PHOSPHORYLATION.
RX PubMed=12124402; DOI=10.1073/pnas.162354599;
RA Yue Y., Chen Z.Y., Gale N.W., Blair-Flynn J., Hu T.J., Yue X., Cooper M.,
RA Crockett D.P., Yancopoulos G.D., Tessarollo L., Zhou R.;
RT "Mistargeting hippocampal axons by expression of a truncated Eph
RT receptor.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:10777-10782(2002).
RN [4]
RP FUNCTION IN INSULIN SECRETION, TISSUE SPECIFICITY, PHOSPHORYLATION, AND
RP DEPHOSPHORYLATION.
RX PubMed=17448994; DOI=10.1016/j.cell.2007.02.044;
RA Konstantinova I., Nikolova G., Ohara-Imaizumi M., Meda P., Kucera T.,
RA Zarbalis K., Wurst W., Nagamatsu S., Lammert E.;
RT "EphA-Ephrin-A-mediated beta cell communication regulates insulin secretion
RT from pancreatic islets.";
RL Cell 129:359-370(2007).
RN [5]
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 [6] {ECO:0007744|PDB:5ZRZ}
RP X-RAY CRYSTALLOGRAPHY (1.89 ANGSTROMS) OF 799-876 IN COMPLEX WITH SAMD5,
RP AND MUTAGENESIS OF LYS-817; VAL-852; LYS-856 AND LYS-857.
RX PubMed=29749928; DOI=10.7554/elife.35677;
RA Wang Y., Shang Y., Li J., Chen W., Li G., Wan J., Liu W., Zhang M.;
RT "Specific Eph receptor-cytoplasmic effector signaling mediated by SAM-SAM
RT domain interactions.";
RL Elife 7:0-0(2018).
CC -!- FUNCTION: Receptor tyrosine kinase which binds promiscuously GPI-
CC anchored ephrin-A 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. Among GPI-anchored ephrin-A
CC ligands, EFNA5 most probably constitutes the cognate/functional ligand
CC for EPHA5. Functions as an axon guidance molecule during development
CC and may be involved in the development of the retinotectal, entorhino-
CC hippocampal and hippocamposeptal pathways. Together with EFNA5 plays
CC also a role in synaptic plasticity in adult brain through regulation of
CC synaptogenesis. In addition to its function in the nervous system, the
CC interaction of EPHA5 with EFNA5 mediates communication between
CC pancreatic islet cells to regulate glucose-stimulated insulin
CC secretion. {ECO:0000269|PubMed:12124402, ECO:0000269|PubMed:17448994}.
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 (By similarity).
CC Interacts (via SAM domain) with SAMD5 (via SAM domain)
CC (PubMed:29749928). {ECO:0000250, ECO:0000269|PubMed:29749928}.
CC -!- INTERACTION:
CC Q60629; P35546-2: Ret; NbExp=5; IntAct=EBI-1267609, EBI-5548911;
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P54757};
CC Single-pass type I membrane protein {ECO:0000255}. Cell projection,
CC axon {ECO:0000250|UniProtKB:P54757}. Cell projection, dendrite
CC {ECO:0000250|UniProtKB:P54756}.
CC -!- TISSUE SPECIFICITY: Specifically expressed in the brain. Highly
CC expressed in hippocampus, tenia tecta, indusium griseum and piriform
CC cortex. The highest level of expression is found in the CA3 region of
CC the hippocampus and the pyramidal cell layer of the piriform cortex. In
CC addition, elevated levels of expression are also found in amygdala,
CC medial septum, nucleus of the diagonal band, and in olfactory bulb.
CC Expressed in pancreatic islet cells (at protein level). Expressed in
CC myogenic progenitor cells (PubMed:27446912).
CC {ECO:0000269|PubMed:17448994, ECO:0000269|PubMed:27446912,
CC ECO:0000269|PubMed:8145300}.
CC -!- DEVELOPMENTAL STAGE: Within the developing nervous system, the
CC expression is very dynamic. At 16.5 dpc expressed predominantly in the
CC primordial cortex of the telencephalon. Besides the midbrain it is also
CC expressed in the hypothalamus, and the neurohypophysis. Non neuronal
CC expression domains include the ectoderm of the branchial arches, the
CC ectoderm and mesenchyme surrounding the dorsal root ganglia, the
CC intervertebral disks, maxillary and mandibulary mesenchymal elements as
CC well as the nasal mesenchyme and ectoderm. In myogenic progenitor
CC cells, expressed at least as early as 11.5 dpc until adulthood
CC (PubMed:27446912). {ECO:0000269|PubMed:27446912,
CC ECO:0000269|PubMed:8145300}.
CC -!- PTM: Phosphorylated. Phosphorylation is stimulated by the ligand EFNA5.
CC Dephosphorylation upon stimulation by glucose, inhibits EPHA5 forward
CC signaling and results in insulin secretion.
CC {ECO:0000269|PubMed:12124402, ECO:0000269|PubMed:17448994}.
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; U07357; AAA17038.1; -; mRNA.
DR EMBL; AC101956; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC114638; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC129220; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC132597; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR CCDS; CCDS19376.1; -.
DR PIR; I48967; I48967.
DR RefSeq; NP_031963.2; NM_007937.3.
DR PDB; 5ZRZ; X-ray; 1.89 A; A=799-876.
DR PDBsum; 5ZRZ; -.
DR AlphaFoldDB; Q60629; -.
DR SMR; Q60629; -.
DR IntAct; Q60629; 3.
DR MINT; Q60629; -.
DR STRING; 10090.ENSMUSP00000060646; -.
DR GlyConnect; 2296; 1 N-Linked glycan (1 site).
DR GlyGen; Q60629; 3 sites, 1 N-linked glycan (1 site).
DR iPTMnet; Q60629; -.
DR PhosphoSitePlus; Q60629; -.
DR SwissPalm; Q60629; -.
DR MaxQB; Q60629; -.
DR PaxDb; Q60629; -.
DR PRIDE; Q60629; -.
DR ProteomicsDB; 275530; -.
DR Antibodypedia; 12603; 538 antibodies from 35 providers.
DR DNASU; 13839; -.
DR Ensembl; ENSMUST00000053733; ENSMUSP00000060646; ENSMUSG00000029245.
DR GeneID; 13839; -.
DR KEGG; mmu:13839; -.
DR UCSC; uc008xwv.3; mouse.
DR CTD; 2044; -.
DR MGI; MGI:99654; Epha5.
DR VEuPathDB; HostDB:ENSMUSG00000029245; -.
DR eggNOG; KOG0196; Eukaryota.
DR GeneTree; ENSGT00940000156266; -.
DR HOGENOM; CLU_000288_141_2_1; -.
DR InParanoid; Q60629; -.
DR TreeFam; TF315363; -.
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; 13839; 1 hit in 28 CRISPR screens.
DR ChiTaRS; Epha5; mouse.
DR PRO; PR:Q60629; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q60629; protein.
DR Bgee; ENSMUSG00000029245; Expressed in cortical plate and 173 other tissues.
DR ExpressionAtlas; Q60629; baseline and differential.
DR Genevisible; Q60629; MM.
DR GO; GO:0005912; C:adherens junction; IDA:MGI.
DR GO; GO:0030424; C:axon; ISS:UniProtKB.
DR GO; GO:0071944; C:cell periphery; IDA:MGI.
DR GO; GO:0030425; C:dendrite; ISS:UniProtKB.
DR GO; GO:0009897; C:external side of plasma membrane; ISO:MGI.
DR GO; GO:0005887; C:integral component of plasma membrane; IBA:GO_Central.
DR GO; GO:0043005; C:neuron projection; IBA:GO_Central.
DR GO; GO:0043025; C:neuronal cell body; ISO:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISO:MGI.
DR GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR GO; GO:0043235; C:receptor complex; IBA:GO_Central.
DR GO; GO:0005791; C:rough endoplasmic reticulum; ISO:MGI.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0005003; F:ephrin receptor activity; ISS:UniProtKB.
DR GO; GO:0005004; F:GPI-linked ephrin receptor activity; IDA:UniProtKB.
DR GO; GO:0019838; F:growth factor binding; ISO:MGI.
DR GO; GO:0004714; F:transmembrane receptor protein tyrosine kinase activity; IBA:GO_Central.
DR GO; GO:0005005; F:transmembrane-ephrin receptor activity; IBA:GO_Central.
DR GO; GO:0007411; P:axon guidance; IDA:UniProtKB.
DR GO; GO:0019933; P:cAMP-mediated signaling; ISS:UniProtKB.
DR GO; GO:0071372; P:cellular response to follicle-stimulating hormone stimulus; IDA:MGI.
DR GO; GO:1904322; P:cellular response to forskolin; IDA:MGI.
DR GO; GO:0060997; P:dendritic spine morphogenesis; ISO:MGI.
DR GO; GO:0048013; P:ephrin receptor signaling pathway; IDA:UniProtKB.
DR GO; GO:0021766; P:hippocampus development; IDA:UniProtKB.
DR GO; GO:0007162; P:negative regulation of cell adhesion; ISO:MGI.
DR GO; GO:0032793; P:positive regulation of CREB transcription factor activity; ISS:UniProtKB.
DR GO; GO:0033674; P:positive regulation of kinase activity; IBA:GO_Central.
DR GO; GO:0032956; P:regulation of actin cytoskeleton organization; IDA:UniProtKB.
DR GO; GO:0043087; P:regulation of GTPase activity; IDA:UniProtKB.
DR GO; GO:0061178; P:regulation of insulin secretion involved in cellular response to glucose stimulus; IDA:UniProtKB.
DR GO; GO:0007169; P:transmembrane receptor protein tyrosine kinase signaling pathway; IBA:GO_Central.
DR CDD; cd00063; FN3; 1.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.60.40.10; -; 1.
DR InterPro; IPR027936; Eph_TM.
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; IPR001426; Tyr_kinase_rcpt_V_CS.
DR Pfam; PF14575; EphA2_TM; 1.
DR Pfam; PF01404; Ephrin_lbd; 1.
DR Pfam; PF00041; fn3; 1.
DR Pfam; PF07714; PK_Tyr_Ser-Thr; 1.
DR Pfam; PF00536; SAM_1; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00615; EPH_lbd; 1.
DR SMART; SM00060; FN3; 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; PS01186; EGF_2; 1.
DR PROSITE; PS51550; EPH_LBD; 1.
DR PROSITE; PS50853; FN3; 1.
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; ATP-binding; Cell membrane; Cell projection; Glycoprotein;
KW Kinase; Membrane; Neurogenesis; Nucleotide-binding; Phosphoprotein;
KW Receptor; Reference proteome; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase.
FT SIGNAL 1..26
FT /evidence="ECO:0000250"
FT CHAIN 27..876
FT /note="Ephrin type-A receptor 5"
FT /id="PRO_0000016813"
FT TOPO_DOM 27..412
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 413..433
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 434..876
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 62..240
FT /note="Eph LBD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00883"
FT DOMAIN 306..400
FT /note="Fibronectin type-III"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00316"
FT DOMAIN 514..775
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT DOMAIN 804..868
FT /note="SAM"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00184"
FT REGION 1..24
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 874..876
FT /note="PDZ-binding"
FT /evidence="ECO:0000255"
FT ACT_SITE 639
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10028"
FT BINDING 520..528
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 546
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 489
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 495
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250"
FT MOD_RES 672
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000255"
FT MOD_RES 821
FT /note="Phosphotyrosine; by autocatalysis"
FT /evidence="ECO:0000250"
FT CARBOHYD 266
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 301
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT MUTAGEN 817
FT /note="K->A: Strongly reduced binding affinity for SAMD5
FT SAM domain."
FT /evidence="ECO:0000269|PubMed:29749928"
FT MUTAGEN 852
FT /note="V->P: Strongly reduced binding affinity for SAMD5
FT SAM domain."
FT /evidence="ECO:0000269|PubMed:29749928"
FT MUTAGEN 856
FT /note="K->A: Strongly reduced binding affinity for SAMD5
FT SAM domain."
FT /evidence="ECO:0000269|PubMed:29749928"
FT MUTAGEN 857
FT /note="K->A: Strongly reduced binding affinity for SAMD5
FT SAM domain."
FT /evidence="ECO:0000269|PubMed:29749928"
FT CONFLICT 532
FT /note="R -> C (in Ref. 1; AAA17038)"
FT /evidence="ECO:0000305"
FT CONFLICT 697
FT /note="S -> A (in Ref. 1; AAA17038)"
FT /evidence="ECO:0000305"
FT CONFLICT 855
FT /note="Q -> QK (in Ref. 1; AAA17038)"
FT /evidence="ECO:0000305"
FT HELIX 809..815
FT /evidence="ECO:0007829|PDB:5ZRZ"
FT HELIX 819..821
FT /evidence="ECO:0007829|PDB:5ZRZ"
FT HELIX 822..827
FT /evidence="ECO:0007829|PDB:5ZRZ"
FT HELIX 833..836
FT /evidence="ECO:0007829|PDB:5ZRZ"
FT HELIX 841..846
FT /evidence="ECO:0007829|PDB:5ZRZ"
FT HELIX 852..871
FT /evidence="ECO:0007829|PDB:5ZRZ"
SQ SEQUENCE 876 AA; 97056 MW; D6539F74DCB6B763 CRC64;
MRGSGPRGAG HRRTQGRGGG DDTPRVPASL AGCYSAPLKG PLWTCLLLCA ALRTLLASPS
NEVNLLDSRT VMGDLGWIAF PKNGWEEIGE VDENYAPIHT YQVCKVMEQN QNNWLLTSWI
SNEGASRIFI ELKFTLRDCN SLPGGLGTCK ETFNMYYFES DDENGRSIKE NQYIKIDTIA
ADESFTELDL GDRVMKLNTE VRDVGPLSKK GFYLAFQDVG ACIALVSVRV YYKKCPSVVR
HLAIFPDTIT GADSSQLLEV SGSCVNHSVT DDPPKMHCSA EGEWLVPIGK CMCKAGYEEK
NGTCQAPSPV TNVKKGKIAK NSISLSWQEP DRPNGIILEY EIKYFEKDQE TSYTIIKSKE
TSITAEGLKP ASVYVFQIRA RTAAGYGVFS RRFEFETTPV SVAASNDQSQ IPIIAVSVTV
GVILLAVMIG FLLSGSCCDC GCGRASSLCA VAHPSLIWRC GYSKAKQDPE EEKMHFHNGH
IKLPGVRTYI DPHTYEDPNQ AVHEFAKEIE ASCITIERVI GAGEFGEVCS GRLKLPGKRE
LPVAIKTLKV GYTEKQRRDF LGEASIMGQF DHPNIIHLEG VVTKSKPVMI VTEYMENGSL
DTFLKKNDGQ FTVIQLVGML RGIAAGMKYL SDMGYVHRDL AARNILINSN LVCKVSDFGL
SRVLEDDPEA AYTTRGGKIP IRWTAPEAIA FRKFTSSSDV WSYGIVMWEV VSYGERPYWE
MTNQDVIKAV EEGYRLPSPM DCPAALYQLM LDCWQKDRNS RPKFDEIVNM LDKLIRNPSS
LKTLVNASSR VSTLLAEHGS LGSGAYRSVG EWLEAIKMGR YTEIFMENGY SSMDAVAQVT
LEDLRRLGVT LVGHQKKIMS SLQEMKVQMV NGMVPV
