P54764 (EPHA4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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 names

Name:	EPHA4
Synonyms:	HEK8, SEK, TYRO1

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	986 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	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. Beside 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. Ref.5
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subunit structure	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. Ref.4
Subcellular location	Cell membrane; Single-pass type I membrane protein By similarity. Cell projection › axon By similarity. Cell projection › dendrite By similarity. Cell junction › synapse › postsynaptic cell membrane › postsynaptic density By similarity. Early endosome By similarity. Note: Clustered upon activation and targeted to early endosome By similarity.
Tissue specificity	Ubiquitous.
Domain	The protein kinase domain mediates interaction with NGEF By similarity.
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily. Contains 1 Eph LBD (Eph ligand-binding) domain. Contains 2 fibronectin type-III domains. Contains 1 protein kinase domain. Contains 1 SAM (sterile alpha motif) domain.

Ontologies

Keywords
Biological process	Cell adhesion Neurogenesis
Cellular component	Cell junction Cell membrane Cell projection Endosome Membrane Postsynaptic cell membrane Synapse
Coding sequence diversity	Polymorphism
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	adult walking behavior Inferred from electronic annotation. Source: Compara cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW corticospinal tract morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB fasciculation of motor neuron axon Inferred from sequence or structural similarity. Source: UniProtKB fasciculation of sensory neuron axon Inferred from sequence or structural similarity. Source: UniProtKB glial cell migration Inferred from electronic annotation. Source: Compara motor neuron axon guidance Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of axon regeneration Inferred from sequence or structural similarity. Source: UniProtKB peptidyl-tyrosine phosphorylation Inferred from direct assay PubMed 12775584. Source: UniProtKB positive regulation of JUN kinase activity Inferred from electronic annotation. Source: Compara positive regulation of Rho guanyl-nucleotide exchange factor activity Inferred from direct assay PubMed 12775584. Source: UniProtKB positive regulation of dendrite morphogenesis Inferred from electronic annotation. Source: Compara protein autophosphorylation Inferred from direct assay PubMed 12775584. Source: UniProtKB regulation of Rac GTPase activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of Rap GTPase activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of astrocyte differentiation Inferred from sequence or structural similarity. Source: UniProtKB regulation of dendritic spine morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	Golgi apparatus Inferred from electronic annotation. Source: Compara axon Inferred from sequence or structural similarity. Source: UniProtKB axon terminus Inferred from electronic annotation. Source: Compara axonal growth cone Inferred from electronic annotation. Source: Compara cell junction Inferred from electronic annotation. Source: UniProtKB-KW cell surface Inferred from electronic annotation. Source: Compara dendrite Inferred from sequence or structural similarity. Source: UniProtKB early endosome membrane Inferred from sequence or structural similarity. Source: UniProtKB endoplasmic reticulum Inferred from electronic annotation. Source: Compara filopodium Inferred from electronic annotation. Source: Compara integral to plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB mitochondrial outer membrane Inferred from electronic annotation. Source: Compara neuromuscular junction Inferred from electronic annotation. Source: Compara perikaryon Inferred from electronic annotation. Source: Compara postsynaptic density Inferred from electronic annotation. Source: UniProtKB-SubCell postsynaptic membrane Inferred from electronic annotation. Source: UniProtKB-KW
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW DH domain binding Inferred from direct assay PubMed 12775584. Source: UniProtKB GPI-linked ephrin receptor activity Inferred from sequence or structural similarity. Source: UniProtKB transmembrane-ephrin receptor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 19

19

Potential

Chain

20 – 986

967

Ephrin type-A receptor 4

PRO_0000016807

Regions

Topological domain

20 – 547

528

Extracellular Potential

Transmembrane

548 – 569

22

Helical; Potential

Topological domain

570 – 986

417

Cytoplasmic Potential

Domain

30 – 209

180

Eph LBD

Domain

328 – 433

106

Fibronectin type-III 1

Domain

441 – 532

92

Fibronectin type-III 2

Domain

621 – 882

262

Protein kinase

Domain

911 – 975

65

SAM

Nucleotide binding

627 – 635

9

ATP By similarity

Motif

984 – 986

3

PDZ-binding Potential

Compositional bias

191 – 325

135

Cys-rich

Sites

Active site

746

1

Proton acceptor By similarity

Binding site

653

1

ATP By similarity

Amino acid modifications

Modified residue

596

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

602

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

779

1

Phosphotyrosine; by autocatalysis Potential

Modified residue

928

1

Phosphotyrosine; by autocatalysis Potential

Glycosylation

235

1

N-linked (GlcNAc...) Potential

Glycosylation

340

1

N-linked (GlcNAc...) Potential

Glycosylation

408

1

N-linked (GlcNAc...) Potential

Glycosylation

545

1

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

269

1

R → Q. Ref.10
Corresponds to variant rs35084379 [ dbSNP | Ensembl ].

VAR_042135

Natural variant

370

1

G → E in a bladder carcinoma NOS sample; somatic mutation. Ref.10

VAR_042136

Natural variant

399

1

S → F in a metastatic melanoma sample; somatic mutation. Ref.10

VAR_042137

Natural variant

953

1

R → K.
Corresponds to variant rs35341687 [ dbSNP | Ensembl ].

VAR_049721

Experimental info

Mutagenesis

40

1

Q → A: 10-fold reduced affinity for EFNB2; when associated with A-42. Ref.9

Mutagenesis

42

1

E → A: 10-fold reduced affinity for EFNB2; when associated with A-40. Ref.9

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

986

Helix Strand Turn

Details...

Beta strand

30 – 35

6

Helix

36 – 38

3

Beta strand

46 – 61

16

Beta strand

65 – 73

9

Beta strand

76 – 78

3

Beta strand

82 – 85

4

Beta strand

97 – 105

9

Helix

108 – 110

3

Turn

115 – 117

3

Beta strand

120 – 130

11

Helix

139 – 141

3

Beta strand

143 – 149

7

Beta strand

154 – 157

4

Beta strand

160 – 162

3

Beta strand

164 – 173

10

Beta strand

178 – 189

12

Beta strand

191 – 202

12

Sequences

	Sequence		Length	Mass (Da)
	P54764 [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 0C39C1152EDDD46F	FASTA	986	109,860
	10 20 30 40 50 60 MAGIFYFALF SCLFGICDAV TGSRVYPANE VTLLDSRSVQ GELGWIASPL EGGWEEVSIM 70 80 90 100 110 120 DEKNTPIRTY QVCNVMEPSQ NNWLRTDWIT REGAQRVYIE IKFTLRDCNS LPGVMGTCKE 130 140 150 160 170 180 TFNLYYYESD NDKERFIREN QFVKIDTIAA DESFTQVDIG DRIMKLNTEI RDVGPLSKKG 190 200 210 220 230 240 FYLAFQDVGA CIALVSVRVF YKKCPLTVRN LAQFPDTITG ADTSSLVEVR GSCVNNSEEK 250 260 270 280 290 300 DVPKMYCGAD GEWLVPIGNC LCNAGHEERS GECQACKIGY YKALSTDATC AKCPPHSYSV 310 320 330 340 350 360 WEGATSCTCD RGFFRADNDA ASMPCTRPPS APLNLISNVN ETSVNLEWSS PQNTGGRQDI 370 380 390 400 410 420 SYNVVCKKCG AGDPSKCRPC GSGVHYTPQQ NGLKTTKVSI TDLLAHTNYT FEIWAVNGVS 430 440 450 460 470 480 KYNPNPDQSV SVTVTTNQAA PSSIALVQAK EVTRYSVALA WLEPDRPNGV ILEYEVKYYE 490 500 510 520 530 540 KDQNERSYRI VRTAARNTDI KGLNPLTSYV FHVRARTAAG YGDFSEPLEV TTNTVPSRII 550 560 570 580 590 600 GDGANSTVLL VSVSGSVVLV VILIAAFVIS RRRSKYSKAK QEADEEKHLN QGVRTYVDPF 610 620 630 640 650 660 TYEDPNQAVR EFAKEIDASC IKIEKVIGVG EFGEVCSGRL KVPGKREICV AIKTLKAGYT 670 680 690 700 710 720 DKQRRDFLSE ASIMGQFDHP NIIHLEGVVT KCKPVMIITE YMENGSLDAF LRKNDGRFTV 730 740 750 760 770 780 IQLVGMLRGI GSGMKYLSDM SYVHRDLAAR NILVNSNLVC KVSDFGMSRV LEDDPEAAYT 790 800 810 820 830 840 TRGGKIPIRW TAPEAIAYRK FTSASDVWSY GIVMWEVMSY GERPYWDMSN QDVIKAIEEG 850 860 870 880 890 900 YRLPPPMDCP IALHQLMLDC WQKERSDRPK FGQIVNMLDK LIRNPNSLKR TGTESSRPNT 910 920 930 940 950 960 ALLDPSSPEF SAVVSVGDWL QAIKMDRYKD NFTAAGYTTL EAVVHVNQED LARIGITAIT 970 980 HQNKILSSVQ AMRTQMQQMH GRMVPV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"cDNA cloning and tissue distribution of five human EPH-like receptor protein-tyrosine kinases." Fox G.M., Holst P.L., Chute H.T., Lindberg R.A., Janssen A.M., Basu R., Welcher A.A. Oncogene 10:897-905(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Fetal brain.
[2]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[3]	"Unified nomenclature for Eph family receptors and their ligands, the ephrins." Eph nomenclature committee Cell 90:403-404(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NOMENCLATURE.
[4]	"The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases." Richter M., Murai K.K., Bourgin C., Pak D.T., Pasquale E.B. J. Neurosci. 27:14205-14215(2007) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH SIPA1L1.
[5]	"Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism." Fu W.Y., Chen Y., Sahin M., Zhao X.S., Shi L., Bikoff J.B., Lai K.O., Yung W.H., Fu A.K., Greenberg M.E., Ip N.Y. Nat. Neurosci. 10:67-76(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF CDK5, AUTOPHOSPHORYLATION.
[6]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[7]	"Crystal structure and NMR binding reveal that two small molecule antagonists target the high affinity ephrin-binding channel of the EphA4 receptor." Qin H., Shi J., Noberini R., Pasquale E.B., Song J. J. Biol. Chem. 283:29473-29484(2008) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 29-209.
[8]	"Structural plasticity of EPH receptor A4 facilitates cross-class ephrin signaling." Bowden T.A., Aricescu A.R., Nettleship J.E., Siebold C., Rahman-Huq N., Owens R.J., Stuart D.I., Jones E.Y. Structure 17:1386-1397(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 30-202 IN COMPLEX WITH EFNA2 OR EFNB2, LIGAND-BINDING.
[9]	"Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph-ephrin binding promiscuity." Qin H., Noberini R., Huan X., Shi J., Pasquale E.B., Song J. J. Biol. Chem. 285:644-654(2010) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS) OF 29-203 IN COMPLEX WITH EFNB2, MUTAGENESIS OF GLN-40 AND GLU-42.
[10]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] GLN-269; GLU-370 AND PHE-399.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

L36645 mRNA. Translation: AAA74246.1.
BC105000 mRNA. Translation: AAI05001.1.
BC105002 mRNA. Translation: AAI05003.1.

IPI

IPI00008318.

PIR

I78844.

RefSeq

NP_004429.1. NM_004438.3.

UniGene

Hs.371218.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2WO1	X-ray	1.85	A/B	30-202	[»]
2WO2	X-ray	2.45	A	30-202	[»]
2WO3	X-ray	2.35	A	30-202	[»]
3CKH	X-ray	2.80	A/B	29-209	[»]
3GXU	X-ray	2.50	A	29-203	[»]

ProteinModelPortal

P54764.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-48294N.

IntAct

P54764. 2 interactions.

STRING

9606.ENSP00000281821.

PTM databases

PhosphoSite

P54764.

Polymorphism databases

DMDM

1711371.

Proteomic databases

PaxDb

P54764.

PeptideAtlas

P54764.

PRIDE

P54764.

Protocols and materials databases

DNASU

2043.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000281821; ENSP00000281821; ENSG00000116106.
ENST00000409938; ENSP00000386829; ENSG00000116106.

GeneID

2043.

KEGG

hsa:2043.

UCSC

uc002vmq.3. human.

Organism-specific databases

CTD

2043.

GeneCards

GC02M222248.

HGNC

HGNC:3388. EPHA4.

HPA

CAB004654.

MIM

602188. gene.

neXtProt

NX_P54764.

PharmGKB

PA27820.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233856.

HOVERGEN

HBG062180.

InParanoid

P54764.

KO

K05105.

OMA

ITAVTHQ.

OrthoDB

EOG48SGS9.

PhylomeDB

P54764.

Enzyme and pathway databases

BRENDA

2.7.10.1. 2681.

Pathway_Interaction_DB

epha_fwdpathway. EPHA forward signaling.
ephrina_ephapathway. EphrinA-EPHA pathway.

Gene expression databases

ArrayExpress

P54764.

Bgee

P54764.

CleanEx

HS_EPHA4.

Genevestigator

P54764.

GermOnline

ENSG00000116106. Homo sapiens.

Family and domain databases

Gene3D

1.10.150.50. 1 hit.
2.60.40.10. 2 hits.

InterPro

IPR001090. Ephrin_rcpt_lig-bd_dom.
IPR003961. Fibronectin_type3.
IPR008979. Galactose-bd-like.
IPR013783. Ig-like_fold.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001660. SAM.
IPR013761. SAM/pointed.
IPR011510. SAM_2.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008266. Tyr_kinase_AS.
IPR020635. Tyr_kinase_cat_dom.
IPR016257. Tyr_kinase_ephrin_rcpt.
IPR001426. Tyr_kinase_rcpt_V_CS.
[Graphical view]

Pfam

PF01404. Ephrin_lbd. 1 hit.
PF00041. fn3. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
PF07647. SAM_2. 1 hit.
[Graphical view]

PIRSF

PIRSF000666. TyrPK_ephrin_receptor. 1 hit.

PRINTS

PR00109. TYRKINASE.

SMART

SM00615. EPH_lbd. 1 hit.
SM00060. FN3. 2 hits.
SM00454. SAM. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

SUPFAM

SSF49265. FN_III-like. 2 hits.
SSF49785. Gal_bind_like. 1 hit.
SSF56112. Kinase_like. 1 hit.
SSF47769. SAM_homology. 1 hit.

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.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P54764.

ChEMBL

CHEMBL3988.

ChiTaRS

EPHA4. human.

EvolutionaryTrace

P54764.

GenomeRNAi

2043.

NextBio

8301.

SOURCE

Search...

Entry information

Entry name

EPHA4_HUMAN

Accession

Primary (citable) accession number: P54764
Secondary accession number(s): Q2M380

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 141 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.