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Protein

Ephrin type-A receptor 4

Gene

EPHA4

Organism
Homo sapiens (Human)
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.1 Publication

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: Ensembl
  • GPI-linked ephrin receptor activity Source: UniProtKB
  • identical protein binding Source: Ensembl
  • kinase activity Source: ARUK-UCL
  • PH domain binding Source: UniProtKB
  • protein kinase activity Source: UniProtKB
  • protein tyrosine kinase binding Source: ARUK-UCL
  • transmembrane-ephrin receptor activity Source: UniProtKB

GO - Biological processi

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 2681
ReactomeiR-HSA-2682334 EPH-Ephrin signaling
R-HSA-3928663 EPHA-mediated growth cone collapse
R-HSA-3928665 EPH-ephrin mediated repulsion of cells
SignaLinkiP54764
SIGNORiP54764

Names & Taxonomyi

Protein namesi
Recommended name:
Ephrin type-A receptor 4 (EC:2.7.10.1)
Alternative name(s):
EPH-like kinase 8
Short name:
EK8
Short name:
hEK8
Tyrosine-protein kinase TYRO1
Tyrosine-protein kinase receptor SEK
Gene namesi
Name:EPHA4
Synonyms:HEK8, SEK, TYRO1
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 2

Organism-specific databases

EuPathDBiHostDB:ENSG00000116106.11
HGNCiHGNC:3388 EPHA4
MIMi602188 gene
neXtProtiNX_P54764

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

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi40Q → A: 10-fold reduced affinity for EFNB2; when associated with A-42. 1 Publication1
Mutagenesisi42E → A: 10-fold reduced affinity for EFNB2; when associated with A-40. 1 Publication1

Organism-specific databases

DisGeNETi2043
MalaCardsiEPHA4
OpenTargetsiENSG00000116106
PharmGKBiPA27820

Chemistry databases

ChEMBLiCHEMBL3988
GuidetoPHARMACOLOGYi1824

Polymorphism and mutation databases

BioMutaiEPHA4
DMDMi1711371

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19Sequence analysisAdd BLAST19
ChainiPRO_000001680720 – 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
Glycosylationi545N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei596Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei602Phosphotyrosine; by autocatalysisBy similarity1
Modified residuei779Phosphotyrosine; by autocatalysisSequence analysis1
Modified residuei928Phosphotyrosine; by autocatalysisSequence analysis1

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

EPDiP54764
MaxQBiP54764
PaxDbiP54764
PeptideAtlasiP54764
PRIDEiP54764
TopDownProteomicsiP54764-1 [P54764-1]

PTM databases

iPTMnetiP54764
PhosphoSitePlusiP54764

Expressioni

Tissue specificityi

Ubiquitous.

Gene expression databases

BgeeiENSG00000116106
CleanExiHS_EPHA4
ExpressionAtlasiP54764 baseline and differential
GenevisibleiP54764 HS

Organism-specific databases

HPAiCAB028368

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 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 (By similarity). 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.By similarity3 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • DH domain binding Source: UniProtKB
  • ephrin receptor binding Source: Ensembl
  • identical protein binding Source: Ensembl
  • PH domain binding Source: UniProtKB
  • protein tyrosine kinase binding Source: ARUK-UCL

Protein-protein interaction databases

BioGridi108357, 49 interactors
DIPiDIP-48294N
IntActiP54764, 10 interactors
STRINGi9606.ENSP00000281821

Chemistry databases

BindingDBiP54764

Structurei

Secondary structure

1986
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi30 – 35Combined sources6
Helixi36 – 38Combined sources3
Turni40 – 42Combined sources3
Beta strandi46 – 60Combined sources15
Beta strandi62 – 65Combined sources4
Beta strandi66 – 73Combined sources8
Beta strandi77 – 79Combined sources3
Beta strandi82 – 85Combined sources4
Beta strandi93 – 96Combined sources4
Beta strandi97 – 105Combined sources9
Helixi108 – 110Combined sources3
Turni115 – 117Combined sources3
Beta strandi120 – 130Combined sources11
Beta strandi131 – 133Combined sources3
Helixi139 – 141Combined sources3
Beta strandi143 – 149Combined sources7
Beta strandi154 – 158Combined sources5
Turni159 – 162Combined sources4
Beta strandi163 – 173Combined sources11
Beta strandi178 – 189Combined sources12
Beta strandi191 – 202Combined sources12
Beta strandi207 – 209Combined sources3
Beta strandi212 – 214Combined sources3
Beta strandi226 – 230Combined sources5
Beta strandi237 – 248Combined sources12
Beta strandi257 – 262Combined sources6
Beta strandi266 – 269Combined sources4
Beta strandi272 – 275Combined sources4
Beta strandi304 – 306Combined sources3
Beta strandi333 – 340Combined sources8
Beta strandi343 – 349Combined sources7
Beta strandi361 – 368Combined sources8
Turni373 – 375Combined sources3
Beta strandi385 – 388Combined sources4
Beta strandi390 – 393Combined sources4
Beta strandi395 – 401Combined sources7
Beta strandi405 – 416Combined sources12
Beta strandi418 – 423Combined sources6
Helixi426 – 428Combined sources3
Beta strandi429 – 435Combined sources7
Beta strandi447 – 452Combined sources6
Beta strandi457 – 461Combined sources5
Beta strandi473 – 483Combined sources11
Beta strandi489 – 500Combined sources12
Beta strandi508 – 517Combined sources10
Beta strandi528 – 531Combined sources4
Turni538 – 540Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2LW8NMR-A29-209[»]
2WO1X-ray1.85A/B30-202[»]
2WO2X-ray2.45A30-202[»]
2WO3X-ray2.35A30-202[»]
3CKHX-ray2.80A/B29-209[»]
3GXUX-ray2.50A29-203[»]
4BK4X-ray3.65A/B20-547[»]
4BK5X-ray4.00A20-547[»]
4BKAX-ray5.30A20-547[»]
4BKFX-ray4.65A/B20-547[»]
4M4PX-ray2.08A27-543[»]
4M4RX-ray3.13A/C/E/G27-543[»]
4W4ZX-ray2.41A/B/C/D29-204[»]
4W50X-ray2.42A/B/C/D29-204[»]
5JR2X-ray1.75A/B/C/D29-204[»]
ProteinModelPortaliP54764
SMRiP54764
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP54764

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.By similarity

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
InParanoidiP54764
KOiK05105
OMAiNGECQAC
OrthoDBiEOG091G00W0
PhylomeDBiP54764
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 1 (identifier: P54764-1) [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
MAGIFYFALF SCLFGICDAV TGSRVYPANE VTLLDSRSVQ GELGWIASPL
60 70 80 90 100
EGGWEEVSIM DEKNTPIRTY QVCNVMEPSQ NNWLRTDWIT REGAQRVYIE
110 120 130 140 150
IKFTLRDCNS LPGVMGTCKE TFNLYYYESD NDKERFIREN QFVKIDTIAA
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 LCNAGHEERS GECQACKIGY YKALSTDATC AKCPPHSYSV
310 320 330 340 350
WEGATSCTCD RGFFRADNDA ASMPCTRPPS APLNLISNVN ETSVNLEWSS
360 370 380 390 400
PQNTGGRQDI SYNVVCKKCG AGDPSKCRPC GSGVHYTPQQ NGLKTTKVSI
410 420 430 440 450
TDLLAHTNYT FEIWAVNGVS KYNPNPDQSV 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 TGTESSRPNT
910 920 930 940 950
ALLDPSSPEF SAVVSVGDWL QAIKMDRYKD NFTAAGYTTL EAVVHVNQED
960 970 980
LARIGITAIT HQNKILSSVQ AMRTQMQQMH GRMVPV
Length:986
Mass (Da):109,860
Last modified:October 1, 1996 - v1
Checksum:i0C39C1152EDDD46F
GO
Isoform 2 (identifier: P54764-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-53: MAGIFYFALFSCLFGICDAVTGSRVYPANEVTLLDSRSVQGELGWIASPLEGG → MK

Note: No experimental confirmation available.
Show »
Length:935
Mass (Da):104,507
Checksum:i588D6FDA5FCCDCE4
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti71Q → P in BAF82995 (PubMed:14702039).Curated1
Sequence conflicti102K → R in BAF82995 (PubMed:14702039).Curated1
Sequence conflicti137I → V in BAG35298 (PubMed:14702039).Curated1
Sequence conflicti362Y → H in BAF82995 (PubMed:14702039).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_042135269R → Q1 PublicationCorresponds to variant dbSNP:rs35084379Ensembl.1
Natural variantiVAR_042136370G → E in a bladder carcinoma NOS sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs756952113Ensembl.1
Natural variantiVAR_042137399S → F in a metastatic melanoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs868224085Ensembl.1
Natural variantiVAR_049721953R → K. Corresponds to variant dbSNP:rs35341687Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0560161 – 53MAGIF…PLEGG → MK in isoform 2. 1 PublicationAdd BLAST53

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
L36645 mRNA Translation: AAA74246.1
AK290306 mRNA Translation: BAF82995.1
AK300772 mRNA Translation: BAH13344.1
AK312380 mRNA Translation: BAG35298.1
AC010899 Genomic DNA No translation available.
AC079834 Genomic DNA No translation available.
BC105000 mRNA Translation: AAI05001.1
BC105002 mRNA Translation: AAI05003.1
CCDSiCCDS2447.1 [P54764-1]
PIRiI78844
RefSeqiNP_001291465.1, NM_001304536.1 [P54764-1]
NP_001291466.1, NM_001304537.1 [P54764-2]
NP_004429.1, NM_004438.4 [P54764-1]
UniGeneiHs.371218

Genome annotation databases

EnsembliENST00000281821; ENSP00000281821; ENSG00000116106 [P54764-1]
ENST00000409938; ENSP00000386829; ENSG00000116106 [P54764-1]
GeneIDi2043
KEGGihsa:2043
UCSCiuc002vmq.4 human [P54764-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Entry informationi

Entry nameiEPHA4_HUMAN
AccessioniPrimary (citable) accession number: P54764
Secondary accession number(s): A8K2P1
, B2R601, B7Z6Q8, Q2M380
Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: May 23, 2018
This is version 187 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 2
    Human chromosome 2: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

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