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Protein

Ephrin type-A receptor 4

Gene

Epha4

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Receptor tyrosine kinase which binds membrane-bound ephrin family ligands residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. The signaling pathway downstream of the receptor is referred to as forward signaling while the signaling pathway downstream of the ephrin ligand is referred to as reverse signaling. Highly promiscuous, it has the unique property among Eph receptors to bind and to be physiologically activated by both GPI-anchored ephrin-A and transmembrane ephrin-B ligands including EFNA1 and EFNB3. Upon activation by ephrin ligands, modulates cell morphology and integrin-dependent cell adhesion through regulation of the Rac, Rap and Rho GTPases activity. Plays an important role in the development of the nervous system controlling different steps of axonal guidance including the establishment of the corticospinal projections. May also control the segregation of motor and sensory axons during neuromuscular circuit development. In addition to its role in axonal guidance plays a role in synaptic plasticity. Activated by EFNA1 phosphorylates CDK5 at 'Tyr-15' which in turn phosphorylates NGEF regulating RHOA and dendritic spine morphogenesis. In the nervous system, plays also a role in repair after injury preventing axonal regeneration and in angiogenesis playing a role in central nervous system vascular formation. Additionally, its promiscuity makes it available to participate in a variety of cell-cell signaling regulating for instance the development of the thymic epithelium.9 Publications

Catalytic activityi

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.PROSITE-ProRule annotation

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei653ATPPROSITE-ProRule annotation1
Active sitei746Proton acceptorPROSITE-ProRule annotation1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi627 – 635ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB-KW
  • DH domain binding Source: UniProtKB
  • ephrin receptor binding Source: MGI
  • GPI-linked ephrin receptor activity Source: UniProtKB
  • identical protein binding Source: IntAct
  • kinase activity Source: MGI
  • PH domain binding Source: MGI
  • protein kinase activity Source: UniProtKB
  • protein tyrosine kinase binding Source: MGI
  • transmembrane-ephrin receptor activity Source: UniProtKB

GO - Biological processi

  • adult walking behavior Source: MGI
  • axon guidance Source: MGI
  • cell adhesion Source: UniProtKB-KW
  • cellular response to amyloid-beta Source: ARUK-UCL
  • corticospinal tract morphogenesis Source: UniProtKB
  • ephrin receptor signaling pathway Source: MGI
  • fasciculation of motor neuron axon Source: UniProtKB
  • fasciculation of sensory neuron axon Source: UniProtKB
  • glial cell migration Source: MGI
  • motor neuron axon guidance Source: UniProtKB
  • negative regulation of axon regeneration Source: UniProtKB
  • negative regulation of long-term synaptic potentiation Source: ARUK-UCL
  • negative regulation of neuron projection development Source: ARUK-UCL
  • negative regulation of proteolysis involved in cellular protein catabolic process Source: MGI
  • nephric duct morphogenesis Source: MGI
  • neuron projection fasciculation Source: ARUK-UCL
  • neuron projection guidance Source: ARUK-UCL
  • peptidyl-tyrosine phosphorylation Source: UniProtKB
  • positive regulation of amyloid-beta formation Source: MGI
  • positive regulation of aspartic-type endopeptidase activity involved in amyloid precursor protein catabolic process Source: MGI
  • positive regulation of dendrite morphogenesis Source: MGI
  • positive regulation of JUN kinase activity Source: BHF-UCL
  • positive regulation of protein tyrosine kinase activity Source: ARUK-UCL
  • positive regulation of Rho guanyl-nucleotide exchange factor activity Source: UniProtKB
  • protein autophosphorylation Source: UniProtKB
  • protein stabilization Source: MGI
  • regulation of astrocyte differentiation Source: UniProtKB
  • regulation of axonogenesis Source: UniProtKB
  • regulation of dendritic spine morphogenesis Source: UniProtKB
  • regulation of GTPase activity Source: UniProtKB
  • regulation of modification of synaptic structure Source: ARUK-UCL

Keywordsi

Molecular functionDevelopmental protein, Kinase, Receptor, Transferase, Tyrosine-protein kinase
Biological processCell adhesion, Neurogenesis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1 3474
ReactomeiR-MMU-2682334 EPH-Ephrin signaling
R-MMU-3928663 EPHA-mediated growth cone collapse
R-MMU-3928665 EPH-ephrin mediated repulsion of cells

Names & Taxonomyi

Protein namesi
Recommended name:
Ephrin type-A receptor 4 (EC:2.7.10.1)
Alternative name(s):
Tyrosine-protein kinase receptor MPK-3
Tyrosine-protein kinase receptor SEK-1
Gene namesi
Name:Epha4
Synonyms:Sek, Sek1
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 1

Organism-specific databases

MGIiMGI:98277 Epha4

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini20 – 547ExtracellularSequence analysisAdd BLAST528
Transmembranei548 – 569HelicalSequence analysisAdd BLAST22
Topological domaini570 – 986CytoplasmicSequence analysisAdd BLAST417

Keywords - Cellular componenti

Cell junction, Cell membrane, Cell projection, Endosome, Membrane, Postsynaptic cell membrane, Synapse

Pathology & Biotechi

Disruption phenotypei

Mice are viable and fertile but display a loss of coordination of limb movement associated with disruptions of cortico-spinal tract. They also display altered development of the thymic epithelium which leads to a defective T-cells development.3 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi635V → M: Kinase dead; loss of autophosphorylation and loss of CHN1 phosphorylation. No effect on interaction with NGEF. 2 Publications1

Chemistry databases

ChEMBLiCHEMBL1293259
GuidetoPHARMACOLOGYi1824

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19Sequence analysisAdd BLAST19
ChainiPRO_000001680820 – 986Ephrin type-A receptor 4Add BLAST967

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Glycosylationi235N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi340N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi408N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei596Phosphotyrosine; by autocatalysis1 Publication1
Modified residuei602Phosphotyrosine; by autocatalysisCombined sources1 Publication1
Modified residuei779Phosphotyrosine; by autocatalysisSequence analysis1
Modified residuei928Phosphotyrosine; by autocatalysisSequence analysis1

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

MaxQBiQ03137
PaxDbiQ03137
PeptideAtlasiQ03137
PRIDEiQ03137

PTM databases

iPTMnetiQ03137
PhosphoSitePlusiQ03137

Expressioni

Tissue specificityi

Highest expression in the adult brain and retina and also detectable in kidney, lung, skeletal muscle and thymus. Not detected in heart and liver. Expressed in myogenic progenitor cells (PubMed:27446912).1 Publication

Developmental stagei

Found in both the 10-day embryonic brain and body tissues. In the embryonic brain, expressed in the developing cortex of the telencephalon and major cortical tracts. Also expressed in the hippocampus, fornix and striatal cells and tracts. In the diencephalon, strongly expressed in thalamus, hypothalamus and thalamo-cortical projection. Also expressed in red nuclei of the mesencephalon and in the cerebellum. In the spinal cord, persistent expression occurs in the dorsal funiculus and ventral gray matter. In myogenic progenitor cells, highly expressed at E11.5 and ceases its expression at the late fetal stage (E17.5) (PubMed:27446912).2 Publications

Gene expression databases

BgeeiENSMUSG00000026235
CleanExiMM_EPHA4
ExpressionAtlasiQ03137 baseline and differential
GenevisibleiQ03137 MM

Interactioni

Subunit structurei

Heterotetramer upon binding of the ligand. The heterotetramer is composed of an ephrin dimer and a receptor dimer. Oligomerization is probably required to induce biological responses. Interacts (phosphorylated at position Tyr-602) with FYN. Interacts (via PDZ motif) with SIPA1L1 (via PDZ domain); controls neuronal morphology through regulation of the RAP1 (RAP1A or RAP1B) and RAP2 (RAP2A, RAP2B or RAP2C) GTPases. Interacts with CDK5, CDK5R1 and NGEF; upon activation by EFNA1 induces NGEF phosphorylation by the kinase CDK5. Interacts with CHN1; effector of EPHA4 in axon guidance linking EPHA4 activation to RAC1 regulation.6 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

Protein-protein interaction databases

BioGridi199471, 4 interactors
DIPiDIP-1019N
IntActiQ03137, 10 interactors
MINTiQ03137
STRINGi10090.ENSMUSP00000027451

Chemistry databases

BindingDBiQ03137

Structurei

Secondary structure

1986
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi618 – 620Combined sources3
Beta strandi621 – 629Combined sources9
Beta strandi631 – 640Combined sources10
Beta strandi648 – 655Combined sources8
Helixi661 – 674Combined sources14
Beta strandi685 – 689Combined sources5
Beta strandi691 – 694Combined sources4
Beta strandi696 – 700Combined sources5
Helixi707 – 712Combined sources6
Turni713 – 716Combined sources4
Helixi720 – 739Combined sources20
Helixi749 – 751Combined sources3
Beta strandi752 – 754Combined sources3
Beta strandi760 – 762Combined sources3
Helixi788 – 790Combined sources3
Helixi793 – 798Combined sources6
Helixi803 – 818Combined sources16
Turni824 – 827Combined sources4
Helixi830 – 838Combined sources9
Helixi851 – 860Combined sources10
Helixi865 – 867Combined sources3
Helixi871 – 883Combined sources13
Helixi885 – 888Combined sources4
Helixi916 – 922Combined sources7
Helixi926 – 928Combined sources3
Helixi929 – 934Combined sources6
Helixi940 – 943Combined sources4
Helixi948 – 954Combined sources7
Helixi959 – 977Combined sources19
Helixi978 – 980Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1B0XX-ray2.00A890-981[»]
2HELX-ray2.35A591-896[»]
2I8Jmodel-@594-888[»]
2XYUX-ray2.12A612-896[»]
2Y6MX-ray1.70A606-896[»]
2Y6OX-ray1.54A606-896[»]
ProteinModelPortaliQ03137
SMRiQ03137
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ03137

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini30 – 209Eph LBDPROSITE-ProRule annotationAdd BLAST180
Domaini328 – 439Fibronectin type-III 1PROSITE-ProRule annotationAdd BLAST112
Domaini440 – 537Fibronectin type-III 2PROSITE-ProRule annotationAdd BLAST98
Domaini621 – 882Protein kinasePROSITE-ProRule annotationAdd BLAST262
Domaini911 – 975SAMPROSITE-ProRule annotationAdd BLAST65

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi984 – 986PDZ-bindingSequence analysis3

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi191 – 325Cys-richAdd BLAST135

Domaini

The protein kinase domain mediates interaction with NGEF.

Sequence similaritiesi

Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily.PROSITE-ProRule annotation

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG0196 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00760000118975
HOGENOMiHOG000233856
HOVERGENiHBG062180
InParanoidiQ03137
KOiK05105
OMAiNGECQAC
OrthoDBiEOG091G00W0
TreeFamiTF315608

Family and domain databases

CDDicd10482 EphR_LBD_A4, 1 hit
cd00063 FN3, 2 hits
Gene3Di2.60.120.260, 1 hit
2.60.40.10, 2 hits
InterProiView protein in InterPro
IPR027936 Eph_TM
IPR034270 EphA4_rcpt_lig-bd
IPR001090 Ephrin_rcpt_lig-bd_dom
IPR003961 FN3_dom
IPR036116 FN3_sf
IPR008979 Galactose-bd-like_sf
IPR013783 Ig-like_fold
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR001660 SAM
IPR013761 SAM/pointed_sf
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR011641 Tyr-kin_ephrin_A/B_rcpt-like
IPR008266 Tyr_kinase_AS
IPR020635 Tyr_kinase_cat_dom
IPR016257 Tyr_kinase_ephrin_rcpt
IPR001426 Tyr_kinase_rcpt_V_CS
PfamiView protein in Pfam
PF14575 EphA2_TM, 1 hit
PF01404 Ephrin_lbd, 1 hit
PF00041 fn3, 2 hits
PF07714 Pkinase_Tyr, 1 hit
PF07647 SAM_2, 1 hit
PIRSFiPIRSF000666 TyrPK_ephrin_receptor, 1 hit
PRINTSiPR00109 TYRKINASE
SMARTiView protein in SMART
SM00615 EPH_lbd, 1 hit
SM01411 Ephrin_rec_like, 1 hit
SM00060 FN3, 2 hits
SM00220 S_TKc, 1 hit
SM00454 SAM, 1 hit
SM00219 TyrKc, 1 hit
SUPFAMiSSF47769 SSF47769, 1 hit
SSF49265 SSF49265, 1 hit
SSF49785 SSF49785, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS51550 EPH_LBD, 1 hit
PS50853 FN3, 2 hits
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00109 PROTEIN_KINASE_TYR, 1 hit
PS00790 RECEPTOR_TYR_KIN_V_1, 1 hit
PS00791 RECEPTOR_TYR_KIN_V_2, 1 hit
PS50105 SAM_DOMAIN, 1 hit

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform Long (identifier: Q03137-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAGIFYFILF SFLFGICDAV TGSRVYPANE VTLLDSRSVQ GELGWIASPL
60 70 80 90 100
EGGWEEVSIM DEKNTPIRTY QVCNVMEASQ NNWLRTDWIT REGAQRVYIE
110 120 130 140 150
IKFTLRDCNS LPGVMGTCKE TFNLYYYESD NDKERFIRES QFGKIDTIAA
160 170 180 190 200
DESFTQVDIG DRIMKLNTEI RDVGPLSKKG FYLAFQDVGA CIALVSVRVF
210 220 230 240 250
YKKCPLTVRN LAQFPDTITG ADTSSLVEVR GSCVNNSEEK DVPKMYCGAD
260 270 280 290 300
GEWLVPIGNC LCNAGHEEQN GECQACKIGY YKALSTDASC AKCPPHSYSV
310 320 330 340 350
WEGATSCTCD RGFFRADNDA ASMPCTRPPS APLNLISNVN ETSVNLEWSS
360 370 380 390 400
PQNTGGRQDI SYNVVCKKCG AGDPSKCRPC GSGVHYTPQQ NGLKTTRVSI
410 420 430 440 450
TDLLAHTNYT FEIWAVNGVS KYNPSPDQSV SVTVTTNQAA PSSIALVQAK
460 470 480 490 500
EVTRYSVALA WLEPDRPNGV ILEYEVKYYE KDQNERSYRI VRTAARNTDI
510 520 530 540 550
KGLNPLTSYV FHVRARTAAG YGDFSEPLEV TTNTVPSRII GDGANSTVLL
560 570 580 590 600
VSVSGSVVLV VILIAAFVIS RRRSKYSKAK QEADEEKHLN QGVRTYVDPF
610 620 630 640 650
TYEDPNQAVR EFAKEIDASC IKIEKVIGVG EFGEVCSGRL KVPGKREICV
660 670 680 690 700
AIKTLKAGYT DKQRRDFLSE ASIMGQFDHP NIIHLEGVVT KCKPVMIITE
710 720 730 740 750
YMENGSLDAF LRKNDGRFTV IQLVGMLRGI GSGMKYLSDM SYVHRDLAAR
760 770 780 790 800
NILVNSNLVC KVSDFGMSRV LEDDPEAAYT TRGGKIPIRW TAPEAIAYRK
810 820 830 840 850
FTSASDVWSY GIVMWEVMSY GERPYWDMSN QDVIKAIEEG YRLPPPMDCP
860 870 880 890 900
IALHQLMLDC WQKERSDRPK FGQIVNMLDK LIRNPNSLKR TGSESSRPNT
910 920 930 940 950
ALLDPSSPEF SAVVSVGDWL QAIKMDRYKD NFTAAGYTTL EAVVHMSQDD
960 970 980
LARIGITAIT HQNKILSSVQ AMRTQMQQMH GRMVPV
Length:986
Mass (Da):109,814
Last modified:July 27, 2011 - v2
Checksum:i89BEB2C7CDB54A55
GO
Isoform Short (identifier: Q03137-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     783-832: Missing.

Note: No experimental confirmation available.
Show »
Length:936
Mass (Da):103,984
Checksum:i3C3EFE4620316DB2
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti145I → T in CAA46268 (PubMed:1281307).Curated1
Sequence conflicti145I → T in AAB25836 (PubMed:1281307).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_002998783 – 832Missing in isoform Short. CuratedAdd BLAST50

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X65138 mRNA Translation: CAA46268.1
X57241 mRNA Translation: CAA40517.1
S57168 mRNA Translation: AAB25836.1
AK147698 mRNA Translation: BAE28081.1
CH466548 Genomic DNA Translation: EDL00429.1
BC052164 mRNA Translation: AAH52164.1
CCDSiCCDS35627.1 [Q03137-1]
PIRiS78059
RefSeqiNP_031962.2, NM_007936.3 [Q03137-1]
UniGeneiMm.400747

Genome annotation databases

EnsembliENSMUST00000027451; ENSMUSP00000027451; ENSMUSG00000026235 [Q03137-1]
ENSMUST00000188797; ENSMUSP00000140954; ENSMUSG00000026235 [Q03137-1]
ENSMUST00000188952; ENSMUSP00000139640; ENSMUSG00000026235 [Q03137-1]
GeneIDi13838
KEGGimmu:13838
UCSCiuc007bpz.1 mouse [Q03137-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiEPHA4_MOUSE
AccessioniPrimary (citable) accession number: Q03137
Secondary accession number(s): Q80VZ2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1994
Last sequence update: July 27, 2011
Last modified: June 20, 2018
This is version 194 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

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