P20827 (EFNA1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ephrin-A1

Alternative name(s):
EPH-related receptor tyrosine kinase ligand 1
Short name=LERK-1
Immediate early response protein B61
Tumor necrosis factor alpha-induced protein 4
Short name=TNF alpha-induced protein 4

Cleaved into the following chain:

1. Ephrin-A1, secreted form

Gene names

Name:	EFNA1
Synonyms:	EPLG1, LERK1, TNFAIP4

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	205 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	Cell surface GPI-bound ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binds promiscuously Eph receptors residing on adjacent cells, leading to contact-dependent bidirectional signaling into neighboring cells. Plays an important role in angiogenesis and tumor neovascularization. The recruitment of VAV2, VAV3 and PI3-kinase p85 subunit by phosphorylated EPHA2 is critical for EFNA1-induced RAC1 GTPase activation and vascular endothelial cell migration and assembly. Exerts anti-oncogenic effects in tumor cells through activation and down-regulation of EPHA2. Activates EPHA2 by inducing tyrosine phosphorylation which leads to its internalization and degradation. Acts as a negative regulator in the tumorigenesis of gliomas by down-regulating EPHA2 and FAK. Can evoke collapse of embryonic neuronal growth cone and regulates dendritic spine morphogenesis. Ref.8 Ref.9
Subunit structure	Monomer. Homodimer. Forms heterodimers with EPHA2. Binds to the receptor tyrosine kinases EPHA2, EPHA3, EPHA4, EPHA5, EPHA6 and EPHA7. Also binds with low affinity to EPHA1. Ref.9 Ref.10
Subcellular location	Cell membrane; Lipid-anchor › GPI-anchor Ref.7 Ref.9. Ephrin-A1, secreted form: Secreted Ref.9.
Tissue specificity	Brain. Down-regulated in primary glioma tissues compared to the normal tissues. The soluble monomeric form is expressed in the glioblastoma multiforme (GBM) and breast cancer cells (at protein level). Ref.8
Induction	By TNF and IL1B/interleukin-1 beta.
Post-translational modification	Undergoes proteolysis by a metalloprotease to give rise to a soluble monomeric form.
Sequence similarities	Belongs to the ephrin family. Contains 1 ephrin RBD (ephrin receptor-binding) domain.

Ontologies

Keywords
Biological process	Angiogenesis
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Tumor suppressor
Domain	Signal
PTM	Disulfide bond GPI-anchor Glycoprotein Lipoprotein
Technical term	3D-structure Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological_process	activation of MAPK activity Inferred from electronic annotation. Source: Compara angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW aortic valve morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL cell migration Inferred from direct assay PubMed 10655584. Source: UniProtKB cell-cell signaling Traceable author statement PubMed 8660976. Source: ProtInc endocardial cushion to mesenchymal transition involved in heart valve formation Inferred from sequence or structural similarity. Source: BHF-UCL ephrin receptor signaling pathway Inferred from direct assay PubMed 10655584. Source: UniProtKB mitral valve morphogenesis Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of dendritic spine morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB negative regulation of epithelial to mesenchymal transition Inferred from sequence or structural similarity. Source: BHF-UCL negative regulation of transcription from RNA polymerase II promoter Inferred from sequence or structural similarity. Source: BHF-UCL neuron differentiation Inferred from electronic annotation. Source: Compara notochord formation Inferred from electronic annotation. Source: Compara positive regulation of peptidyl-tyrosine phosphorylation Inferred from direct assay PubMed 10655584. Source: UniProtKB regulation of angiogenesis Inferred from electronic annotation. Source: Compara regulation of axonogenesis Inferred from electronic annotation. Source: Compara regulation of blood vessel endothelial cell migration Inferred from electronic annotation. Source: Compara regulation of cell adhesion mediated by integrin Inferred from direct assay PubMed 10655584. Source: UniProtKB substrate adhesion-dependent cell spreading Inferred from direct assay PubMed 10655584. Source: UniProtKB
Cellular_component	anchored to plasma membrane Inferred from electronic annotation. Source: Compara extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Traceable author statement PubMed 8660976. Source: ProtInc
Molecular_function	ephrin receptor binding Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
EPHA2	P29317	5	EBI-715194,EBI-702104

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: P20827-1)

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.

Isoform 2 (identifier: P20827-2)

The sequence of this isoform differs from the canonical sequence as follows:
     131-152: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 18

18

Ref.6

Chain

19 – 182

164

Ephrin-A1

PRO_0000008353

Chain

19 – ?

Ephrin-A1, secreted form

PRO_0000389630

Propeptide

183 – 205

23

Removed in mature form Potential

PRO_0000008354

Regions

Domain

19 – 151

133

Ephrin RBD

Amino acid modifications

Lipidation

182

1

GPI-anchor amidated serine Potential

Glycosylation

26

1

N-linked (GlcNAc...) Potential

Disulfide bond

51 ↔ 92

Ref.10 Ref.11

Disulfide bond

80 ↔ 140

Ref.10 Ref.11

Natural variations

Alternative sequence

131 – 152

22

Missing in isoform 2.

VSP_017543

Natural variant

159

1

D → V. Ref.1 Ref.2 Ref.4 Ref.5
Corresponds to variant rs4745 [ dbSNP | Ensembl ].

VAR_014791

Experimental info

Sequence conflict

180

1

G → A in AAH32698. Ref.5

Secondary structure

1

.

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205

Helix Strand Turn

Details...

Beta strand

20 – 24

5

Helix

30 – 32

3

Beta strand

38 – 41

4

Beta strand

46 – 50

5

Helix

61 – 63

3

Beta strand

67 – 72

6

Helix

74 – 79

6

Helix

85 – 87

3

Beta strand

88 – 92

5

Beta strand

98 – 100

3

Beta strand

103 – 107

5

Beta strand

125 – 134

10

Beta strand

142 – 147

6

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified August 30, 2005. Version 2. Checksum: EFF026BF4C12461F	FASTA	205	23,787
	10 20 30 40 50 60 MEFLWAPLLG LCCSLAAADR HTVFWNSSNP KFRNEDYTIH VQLNDYVDII CPHYEDHSVA 70 80 90 100 110 120 DAAMEQYILY LVEHEEYQLC QPQSKDQVRW QCNRPSAKHG PEKLSEKFQR FTPFTLGKEF 130 140 150 160 170 180 KEGHSYYYIS KPIHQHEDRC LRLKVTVSGK ITHSPQAHDN PQEKRLAADD PEVRVLHSIG 190 200 HSAAPRLFPL AWTVLLLPLL LLQTP
	Isoform 2 [UniParc]. Checksum: 8B9A70B6402577BD	FASTA	183	21,246
	10 20 30 40 50 60 MEFLWAPLLG LCCSLAAADR HTVFWNSSNP KFRNEDYTIH VQLNDYVDII CPHYEDHSVA 70 80 90 100 110 120 DAAMEQYILY LVEHEEYQLC QPQSKDQVRW QCNRPSAKHG PEKLSEKFQR FTPFTLGKEF 130 140 150 160 170 180 KEGHSYYYIS HSPQAHDNPQ EKRLAADDPE VRVLHSIGHS AAPRLFPLAW TVLLLPLLLL QTP

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel immediate-early response gene of endothelium is induced by cytokines and encodes a secreted protein." Holzman L.B., Marks R.M., Dixit V.M. Mol. Cell. Biol. 10:5830-5838(1990) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT VAL-159.
[2]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT VAL-159.
[3]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], VARIANT VAL-159.
[5]	"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] (ISOFORM 1), VARIANT VAL-159. Tissue: Liver.
[6]	"Signal peptide prediction based on analysis of experimentally verified cleavage sites." Zhang Z., Henzel W.J. Protein Sci. 13:2819-2824(2004) [PubMed] [Europe PMC] [Abstract] Cited for: PROTEIN SEQUENCE OF 19-33.
[7]	"Ligands for the receptor tyrosine kinases hek and elk: isolation of cDNAs encoding a family of proteins." Kozlosky C.J., Maraskovsky E., McGrew J.T., Vanden Bos T., Teepe M., Lyman S.D., Srinivasan S., Fletcher F.A., Gayle R.B. III, Cerretti D.P., Beckmann M.P. Oncogene 10:299-306(1995) [PubMed] [Europe PMC] [Abstract] Cited for: GPI-ANCHOR.
[8]	"Ephrin-A1 is a negative regulator in glioma through down-regulation of EphA2 and FAK." Liu D.-P., Wang Y., Koeffler H.P., Xie D. Int. J. Oncol. 30:865-871(2007) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, TISSUE SPECIFICITY.
[9]	"Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor." Wykosky J., Palma E., Gibo D.M., Ringler S., Turner C.P., Debinski W. Oncogene 27:7260-7273(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE.
[10]	"Ligand recognition by A-class Eph receptors: crystal structures of the EphA2 ligand-binding domain and the EphA2/ephrin-A1 complex." Himanen J.P., Goldgur Y., Miao H., Myshkin E., Guo H., Buck M., Nguyen M., Rajashankar K.R., Wang B., Nikolov D.B. EMBO Rep. 10:722-728(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 19-147 IN COMPLEX WITH EPHA2, SUBUNIT, DISULFIDE BOND, GLYCOSYLATION AT ASN-26.
[11]	"Ephrin A1 bound to the ligand binding domain of the human ephrin A2 (EPHA2) receptor protein kinase." Structural genomics consortium (SGC) Submitted (FEB-2009) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 19-171 IN COMPLEX WITH EPHA2, DISULFIDE BONDS.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

M57730 mRNA. Translation: AAA58388.1.
CR457416 mRNA. Translation: CAG33697.1.
AL691442 Genomic DNA. Translation: CAI15319.1.
AL691442 Genomic DNA. Translation: CAI15320.1.
CH471121 Genomic DNA. Translation: EAW53131.1.
CH471121 Genomic DNA. Translation: EAW53132.1.
BC032698 mRNA. Translation: AAH32698.1.
BC095432 mRNA. Translation: AAH95432.1.

IPI

IPI00025840.
IPI00377015.

PIR

A36377.

RefSeq

NP_004419.2. NM_004428.2.
NP_872626.1. NM_182685.1.

UniGene

Hs.516664.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3CZU	X-ray	2.65	B	17-171	[»]
3HEI	X-ray	2.00	B/D/F/H/J/L/N/P	18-147	[»]
3MBW	X-ray	2.81	B	17-171	[»]

ProteinModelPortal

P20827.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-98N.

IntAct

P20827. 5 interactions.

MINT

MINT-1393983.

STRING

9606.ENSP00000357392.

PTM databases

PhosphoSite

P20827.

Polymorphism databases

DMDM

73920206.

Proteomic databases

PaxDb

P20827.

PRIDE

P20827.

Protocols and materials databases

DNASU

1942.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000368406; ENSP00000357391; ENSG00000169242.
ENST00000368407; ENSP00000357392; ENSG00000169242.

GeneID

1942.

KEGG

hsa:1942.

UCSC

uc001fhh.3. human.
uc001fhi.3. human.

Organism-specific databases

CTD

1942.

GeneCards

GC01P155099.

H-InvDB

HIX0116282.
HIX0116386.

HGNC

HGNC:3221. EFNA1.

HPA

CAB032498.

MIM

191164. gene.

neXtProt

NX_P20827.

PharmGKB

PA27656.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG296825.

HOGENOM

HOG000234373.

HOVERGEN

HBG051447.

InParanoid

P20827.

KO

K05462.

OMA

PIHHQED.

OrthoDB

EOG4D52ZP.

PhylomeDB

P20827.

Enzyme and pathway databases

Pathway_Interaction_DB

epha_fwdpathway. EPHA forward signaling.
epha2_fwdpathway. EPHA2 forward signaling.

Gene expression databases

Bgee

P20827.

CleanEx

HS_EFNA1.

Genevestigator

P20827.

GermOnline

ENSG00000169242. Homo sapiens.

Family and domain databases

Gene3D

2.60.40.420. 1 hit.

InterPro

IPR008972. Cupredoxin.
IPR001799. Ephrin.
IPR019765. Ephrin_CS.
[Graphical view]

PANTHER

PTHR11304. PTHR11304. 1 hit.

Pfam

PF00812. Ephrin. 1 hit.
[Graphical view]

PRINTS

PR01347. EPHRIN.

ProDom

PD002533. Ephrin. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SUPFAM

SSF49503. Cupredoxin. 1 hit.

PROSITE

PS01299. EPHRIN_RBD_1. 1 hit.
PS51551. EPHRIN_RBD_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

EvolutionaryTrace

P20827.

GenomeRNAi

1942.

NextBio

7865.

SOURCE

Search...

Entry information

Entry name

EFNA1_HUMAN

Accession

Primary (citable) accession number: P20827
Secondary accession number(s): D3DV86 , Q5SR60, Q5SR61, Q6I9T9, Q8N578

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1991
Last sequence update:	August 30, 2005
Last modified:	May 1, 2013
This is version 130 of the entry and version 2 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.