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P29317 (EPHA2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 172. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Ephrin type-A receptor 2

EC=2.7.10.1
Alternative name(s):
Epithelial cell kinase
Tyrosine-protein kinase receptor ECK
Gene names
Name:EPHA2
Synonyms:ECK
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length976 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is further processed into a mature form.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Receptor tyrosine kinase which binds promiscuously membrane-bound ephrin-A 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. Activated by the ligand ephrin-A1/EFNA1 regulates migration, integrin-mediated adhesion, proliferation and differentiation of cells. Regulates cell adhesion and differentiation through DSG1/desmoglein-1 and inhibition of the ERK1/ERK2 (MAPK3/MAPK1, respectively) signaling pathway. May also participate in UV radiation-induced apoptosis and have a ligand-independent stimulatory effect on chemotactic cell migration. During development, may function in distinctive aspects of pattern formation and subsequently in development of several fetal tissues. Involved for instance in angiogenesis, in early hindbrain development and epithelial proliferation and branching morphogenesis during mammary gland development. Engaged by the ligand ephrin-A5/EFNA5 may regulate lens fiber cells shape and interactions and be important for lens transparency development and maintenance. With ephrin-A2/EFNA2 may play a role in bone remodeling through regulation of osteoclastogenesis and osteoblastogenesis. Ref.6 Ref.9 Ref.12 Ref.16 Ref.20 Ref.21 Ref.26

Catalytic activity

ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate. Ref.1

Subunit structure

Homodimer. Interacts with SLA. Interacts (phosphorylated form) with VAV2, VAV3 and PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3); critical for the EFNA1-induced activation of RAC1 which stimulates cell migration By similarity. Interacts with INPPL1; regulates activated EPHA2 endocytosis and degradation. Interacts (inactivated form) with PTK2/FAK1 and interacts (EFNA1 ligand-activated form) with PTPN11; regulates integrin-mediated adhesion. Interacts with ARHGEF16, DOCK4 and ELMO2; mediates ligand-independent activation of RAC1 which stimulates cell migration. Interacts with CLDN4; phosphorylates CLDN4 and may regulate tight junctions. Interacts with ACP1. Interacts (via SAM domain) with ANKS1A (via SAM domain). Interacts with human herpes virus 8/HHV-8 glycoprotein L/gL and glycoprotein H/gH heterodimer; this interaction triggers EPHA2 phosphorylation and endocytosis, allowing virus entry. Interacts with CEMIP. Interacts with NCK1; may regulate EPHA2 activity in cell migration and adhesion. Ref.6 Ref.8 Ref.9 Ref.11 Ref.20 Ref.24 Ref.25 Ref.26 Ref.27 Ref.30

Subcellular location

Cell membrane; Single-pass type I membrane protein. Cell projectionruffle membrane; Single-pass type I membrane protein. Cell projectionlamellipodium membrane; Single-pass type I membrane protein. Cell junctionfocal adhesion. Note: Present at regions of cell-cell contacts but also at the leading edge of migrating cells. Ref.6 Ref.14 Ref.16 Ref.21

Tissue specificity

Expressed in brain and glioma tissue and glioma cell lines (at protein level). Expressed most highly in tissues that contain a high proportion of epithelial cells, e.g. skin, intestine, lung, and ovary. Ref.10

Induction

Up-regulated by UV irradiation via a TP53-independent, MAPK-dependent mechanism. Ref.12

Post-translational modification

Autophosphorylates. Phosphorylated on tyrosine upon binding and activation by EFNA1. Phosphorylated residues Tyr-588 and Tyr-594 are required for binding VAV2 and VAV3 while phosphorylated residues Tyr-735 and Tyr-930 are required for binding PI3-kinase p85 subunit (PIK3R1, PIK3R2 or PIK3R3). These phosphorylated residues are critical for recruitment of VAV2 and VAV3 and PI3-kinase p85 subunit which transduce downstream signaling to activate RAC1 GTPase and cell migration. Dephosphorylation of Tyr-930 by PTPRF prevents the interaction of EPHA2 with NCK1. Phosphorylated at Ser-897 by PKB; serum-induced phosphorylation which targets EPHA2 to the cell leading edge and stimulates cell migration. Phosphorylation by PKB is inhibited by EFNA1-activated EPHA2 which regulates PKB activity via a reciprocal regulatory loop. Dephosphorylated by ACP1. Ref.1 Ref.6 Ref.8 Ref.14 Ref.16 Ref.26

Ubiquitinated by CHIP/STUB1. Ubiquitination is regulated by the HSP90 chaperone and regulates the receptor stability and activity through proteasomal degradation. ANKS1A prevents ubiquitination and degradation By similarity. Ref.18

Involvement in disease

Cataract 6, multiple types (CTRCT6) [MIM:116600]: An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT6 includes posterior polar and age-related cortical cataracts, among others. Posterior polar cataract is a subcapsular opacity, usually disk-shaped, located at the back of the lens. Age-related cortical cataract is a developmental punctate opacity restricted to the cortex. The cataract is white or cerulean, increases in number with age, but rarely affects vision.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16 Ref.34 Ref.35 Ref.36 Ref.37

Overexpressed in several cancer types and promotes malignancy. Ref.16

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 processAngiogenesis
Apoptosis
Cell adhesion
Differentiation
Host-virus interaction
   Cellular componentCell junction
Cell membrane
Cell projection
Membrane
   Coding sequence diversityPolymorphism
   DiseaseCataract
Disease mutation
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionKinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMDisulfide bond
Glycoprotein
Phosphoprotein
Ubl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processactivation of Rac GTPase activity

Inferred from mutant phenotype Ref.20. Source: UniProtKB

angiogenesis

Inferred from electronic annotation. Source: UniProtKB-KW

axial mesoderm formation

Inferred from electronic annotation. Source: Ensembl

bone remodeling

Inferred from sequence or structural similarity. Source: UniProtKB

branching involved in mammary gland duct morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

cell adhesion

Inferred from electronic annotation. Source: UniProtKB-KW

cell chemotaxis

Inferred from mutant phenotype Ref.16Ref.20. Source: UniProtKB

ephrin receptor signaling pathway

Inferred from direct assay Ref.6Ref.21. Source: UniProtKB

intrinsic apoptotic signaling pathway in response to DNA damage

Inferred from direct assay Ref.12. Source: UniProtKB

keratinocyte differentiation

Inferred from mutant phenotype Ref.21. Source: UniProtKB

lens fiber cell morphogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

mammary gland epithelial cell proliferation

Inferred from sequence or structural similarity. Source: UniProtKB

multicellular organismal development

Traceable author statement PubMed 7918100. Source: ProtInc

negative regulation of protein kinase B signaling

Inferred from direct assay Ref.16. Source: UniProtKB

neural tube development

Inferred from electronic annotation. Source: Ensembl

neuron differentiation

Inferred from electronic annotation. Source: Ensembl

notochord cell development

Inferred from electronic annotation. Source: Ensembl

notochord formation

Inferred from electronic annotation. Source: Ensembl

osteoblast differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

osteoclast differentiation

Inferred from sequence or structural similarity. Source: UniProtKB

peptidyl-tyrosine phosphorylation

Inferred from direct assay Ref.6. Source: GOC

positive regulation of establishment of protein localization to plasma membrane

Inferred from mutant phenotype Ref.20. Source: UniProtKB

post-anal tail morphogenesis

Inferred from electronic annotation. Source: Ensembl

protein kinase B signaling

Inferred from direct assay Ref.16. Source: UniProtKB

regulation of ERK1 and ERK2 cascade

Inferred from mutant phenotype Ref.21. Source: UniProtKB

regulation of angiogenesis

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of blood vessel endothelial cell migration

Inferred from sequence or structural similarity. Source: UniProtKB

regulation of cell adhesion mediated by integrin

Inferred from direct assay Ref.6. Source: UniProtKB

regulation of lamellipodium assembly

Inferred from mutant phenotype Ref.16. Source: UniProtKB

response to growth factor

Inferred from mutant phenotype Ref.16. Source: UniProtKB

skeletal system development

Inferred from electronic annotation. Source: Ensembl

vasculogenesis

Inferred from electronic annotation. Source: Ensembl

viral process

Inferred from electronic annotation. Source: UniProtKB-KW

   Cellular_componentfocal adhesion

Inferred from direct assay Ref.6. Source: UniProtKB

integral component of plasma membrane

Inferred from direct assay Ref.6. Source: UniProtKB

lamellipodium membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

leading edge membrane

Inferred from direct assay Ref.16Ref.20. Source: UniProtKB

plasma membrane

Inferred from direct assay Ref.14Ref.21. Source: UniProtKB

ruffle membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

ephrin receptor activity

Inferred from electronic annotation. Source: InterPro

protein binding

Inferred from physical interaction PubMed 15777695Ref.20Ref.26. Source: UniProtKB

transmembrane receptor protein tyrosine kinase activity

Inferred from direct assay Ref.6. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2323 Potential
Chain24 – 976953Ephrin type-A receptor 2
PRO_0000016800

Regions

Topological domain24 – 537514Extracellular Potential
Transmembrane538 – 55821Helical; Potential
Topological domain559 – 976418Cytoplasmic Potential
Domain28 – 206179Eph LBD
Domain328 – 432105Fibronectin type-III 1
Domain438 – 52992Fibronectin type-III 2
Domain613 – 875263Protein kinase
Domain904 – 96865SAM
Nucleotide binding619 – 6279ATP By similarity
Region1 – 206206Mediates interaction with CLDN4
Region606 – 906301Mediates interaction with ARHGEF16 and ELMO2
Region886 – 97691Negatively regulates interaction with ARHGEF16
Motif974 – 9763PDZ-binding Potential
Compositional bias188 – 325138Cys-rich

Sites

Active site7391Proton acceptor By similarity
Binding site6461ATP By similarity

Amino acid modifications

Modified residue1531Phosphoserine
Modified residue3731Phosphoserine
Modified residue5701Phosphoserine Ref.13 Ref.15 Ref.19
Modified residue5751Phosphotyrosine
Modified residue5791Phosphoserine Ref.13
Modified residue5871Phosphothreonine
Modified residue5881Phosphotyrosine; by autocatalysis By similarity
Modified residue5931Phosphothreonine
Modified residue5941Phosphotyrosine; by autocatalysis
Modified residue6281Phosphotyrosine Ref.19
Modified residue6471Phosphothreonine Ref.13 Ref.19
Modified residue7351Phosphotyrosine; by autocatalysis By similarity
Modified residue7711Phosphothreonine
Modified residue7721Phosphotyrosine; by autocatalysis
Modified residue7901Phosphoserine
Modified residue7911Phosphotyrosine
Modified residue8691Phosphoserine Ref.19
Modified residue8801Phosphoserine
Modified residue8921Phosphoserine Ref.15
Modified residue8971Phosphoserine; by PKB Ref.16
Modified residue8981Phosphothreonine
Modified residue8991Phosphoserine
Modified residue9011Phosphoserine Ref.15
Modified residue9101Phosphoserine
Modified residue9211Phosphotyrosine; by autocatalysis Potential
Modified residue9301Phosphotyrosine Ref.26
Modified residue9601Phosphotyrosine
Glycosylation4071N-linked (GlcNAc...) Potential
Glycosylation4351N-linked (GlcNAc...) Ref.17
Disulfide bond70 ↔ 188 Ref.30 Ref.31
Disulfide bond105 ↔ 115 Ref.30 Ref.31

Natural variations

Natural variant991K → N.
Corresponds to variant rs1058372 [ dbSNP | Ensembl ].
VAR_055989
Natural variant3911G → R. Ref.33
Corresponds to variant rs34192549 [ dbSNP | Ensembl ].
VAR_042121
Natural variant5111T → M. Ref.33
Corresponds to variant rs55747232 [ dbSNP | Ensembl ].
VAR_042122
Natural variant5681R → H. Ref.33
Corresponds to variant rs56198600 [ dbSNP | Ensembl ].
VAR_042123
Natural variant6311M → T.
Corresponds to variant rs34021505 [ dbSNP | Ensembl ].
VAR_055990
Natural variant7211R → Q in CTRCT6; retained in the cytoplasm and constitutively active it alters EPHA2 signaling. Ref.36
Corresponds to variant rs116506614 [ dbSNP | Ensembl ].
VAR_062532
Natural variant7771G → S in a gastric adenocarcinoma sample; somatic mutation. Ref.33
VAR_042124
Natural variant8761R → H. Ref.33
Corresponds to variant rs35903225 [ dbSNP | Ensembl ].
VAR_042125
Natural variant9401T → I in CTRCT6; reduced protein stability and reduced ability to stimulate cell migration in absence of its ephrin ligand. Ref.35 Ref.37
VAR_058907
Natural variant9481G → W in CTRCT6; reduced protein stability and reduced ability to stimulate cell migration in absence of its ephrin ligand. Ref.34 Ref.37
VAR_058908

Experimental info

Mutagenesis1031R → E: Significantly reduced response to EFNA1. Ref.30
Mutagenesis6461K → M: Loss of kinase activity. Ref.9
Mutagenesis7391D → N: Increases serum-induced chemotaxis. Loss of EFNA1-dependent regulation of cell migration. Ref.16
Mutagenesis8971S → A or D: Loss of serum-induced phosphorylation by PKB. Loss of serum-induced chemotaxis. Ref.16
Sequence conflict94 – 996IFIELK → NNFELN in AAA53375. Ref.1

Secondary structure

.................................................................................................................................................... 976
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
P29317 [UniParc].

Last modified May 5, 2009. Version 2.
Checksum: 845D7E1BBCCAACCC

FASTA976108,266
        10         20         30         40         50         60 
MELQAARACF ALLWGCALAA AAAAQGKEVV LLDFAAAGGE LGWLTHPYGK GWDLMQNIMN 

        70         80         90        100        110        120 
DMPIYMYSVC NVMSGDQDNW LRTNWVYRGE AERIFIELKF TVRDCNSFPG GASSCKETFN 

       130        140        150        160        170        180 
LYYAESDLDY GTNFQKRLFT KIDTIAPDEI TVSSDFEARH VKLNVEERSV GPLTRKGFYL 

       190        200        210        220        230        240 
AFQDIGACVA LLSVRVYYKK CPELLQGLAH FPETIAGSDA PSLATVAGTC VDHAVVPPGG 

       250        260        270        280        290        300 
EEPRMHCAVD GEWLVPIGQC LCQAGYEKVE DACQACSPGF FKFEASESPC LECPEHTLPS 

       310        320        330        340        350        360 
PEGATSCECE EGFFRAPQDP ASMPCTRPPS APHYLTAVGM GAKVELRWTP PQDSGGREDI 

       370        380        390        400        410        420 
VYSVTCEQCW PESGECGPCE ASVRYSEPPH GLTRTSVTVS DLEPHMNYTF TVEARNGVSG 

       430        440        450        460        470        480 
LVTSRSFRTA SVSINQTEPP KVRLEGRSTT SLSVSWSIPP PQQSRVWKYE VTYRKKGDSN 

       490        500        510        520        530        540 
SYNVRRTEGF SVTLDDLAPD TTYLVQVQAL TQEGQGAGSK VHEFQTLSPE GSGNLAVIGG 

       550        560        570        580        590        600 
VAVGVVLLLV LAGVGFFIHR RRKNQRARQS PEDVYFSKSE QLKPLKTYVD PHTYEDPNQA 

       610        620        630        640        650        660 
VLKFTTEIHP SCVTRQKVIG AGEFGEVYKG MLKTSSGKKE VPVAIKTLKA GYTEKQRVDF 

       670        680        690        700        710        720 
LGEAGIMGQF SHHNIIRLEG VISKYKPMMI ITEYMENGAL DKFLREKDGE FSVLQLVGML 

       730        740        750        760        770        780 
RGIAAGMKYL ANMNYVHRDL AARNILVNSN LVCKVSDFGL SRVLEDDPEA TYTTSGGKIP 

       790        800        810        820        830        840 
IRWTAPEAIS YRKFTSASDV WSFGIVMWEV MTYGERPYWE LSNHEVMKAI NDGFRLPTPM 

       850        860        870        880        890        900 
DCPSAIYQLM MQCWQQERAR RPKFADIVSI LDKLIRAPDS LKTLADFDPR VSIRLPSTSG 

       910        920        930        940        950        960 
SEGVPFRTVS EWLESIKMQQ YTEHFMAAGY TAIEKVVQMT NDDIKRIGVR LPGHQKRIAY 

       970 
SLLGLKDQVN TVGIPI 

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References

« Hide 'large scale' references
[1]"cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases."
Lindberg R.A., Hunter T.
Mol. Cell. Biol. 10:6316-6324(1990) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], CATALYTIC ACTIVITY, AUTOPHOSPHORYLATION.
Tissue: Epithelium.
[2]"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. expand/collapse author list , 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].
[3]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. expand/collapse author list , 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 (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]"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: Pancreas.
[5]"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.
[6]"Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation."
Miao H., Burnett E., Kinch M., Simon E., Wang B.
Nat. Cell Biol. 2:62-69(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INTEGRIN-MEDIATED CELL ADHESION, FUNCTION IN CELL MIGRATION, PHOSPHORYLATION, INTERACTION WITH PTK2/FAK1 AND PTPN11, SUBCELLULAR LOCATION.
[7]"EphA2 overexpression causes tumorigenesis of mammary epithelial cells."
Zelinski D.P., Zantek N.D., Stewart J.C., Irizarry A.R., Kinch M.S.
Cancer Res. 61:2301-2306(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: ONCOGENICITY.
[8]"Regulation of the EphA2 kinase by the low molecular weight tyrosine phosphatase induces transformation."
Kikawa K.D., Vidale D.R., Van Etten R.L., Kinch M.S.
J. Biol. Chem. 277:39274-39279(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ACP1, DEPHOSPHORYLATION BY ACP1.
[9]"EphA2 phosphorylates the cytoplasmic tail of Claudin-4 and mediates paracellular permeability."
Tanaka M., Kamata R., Sakai R.
J. Biol. Chem. 280:42375-42382(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL-CELL INTERACTION, INTERACTION WITH CLDN4, MUTAGENESIS OF LYS-646.
[10]"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: TISSUE SPECIFICITY.
[11]"Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation."
Zhuang G., Hunter S., Hwang Y., Chen J.
J. Biol. Chem. 282:2683-2694(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH INPPL1.
[12]"EphA2 is an essential mediator of UV radiation-induced apoptosis."
Zhang G., Njauw C.-N., Park J.M., Naruse C., Asano M., Tsao H.
Cancer Res. 68:1691-1696(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN APOPTOSIS, INDUCTION BY UV.
[13]"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M.
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-570; SER-579 AND THR-647, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[14]"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: SUBCELLULAR LOCATION, PHOSPHORYLATION.
[15]"A quantitative atlas of mitotic phosphorylation."
Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P.
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-570; SER-892 AND SER-901, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[16]"EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt."
Miao H., Li D.Q., Mukherjee A., Guo H., Petty A., Cutter J., Basilion J.P., Sedor J., Wu J., Danielpour D., Sloan A.E., Cohen M.L., Wang B.
Cancer Cell 16:9-20(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: DISEASE, FUNCTION IN CELL MIGRATION, SUBCELLULAR LOCATION, MUTAGENESIS OF ASP-739 AND SER-897, PHOSPHORYLATION AT SER-897 BY PKB.
[17]"Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry."
Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.
J. Proteome Res. 8:651-661(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-435.
Tissue: Liver.
[18]"Hsp90 is an essential regulator of EphA2 receptor stability and signaling: implications for cancer cell migration and metastasis."
Annamalai B., Liu X., Gopal U., Isaacs J.S.
Mol. Cancer Res. 7:1021-1032(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION BY STUB1.
[19]"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: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-570; TYR-628; THR-647 AND SER-869, IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[20]"Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism."
Hiramoto-Yamaki N., Takeuchi S., Ueda S., Harada K., Fujimoto S., Negishi M., Katoh H.
J. Cell Biol. 190:461-477(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION, INTERACTION WITH ARHGEF16; DOCK4 AND ELMO2.
[21]"Ligand targeting of EphA2 enhances keratinocyte adhesion and differentiation via desmoglein 1."
Lin S., Gordon K., Kaplan N., Getsios S.
Mol. Biol. Cell 21:3902-3914(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN KERATINOCYTE ADHESION AND DIFFERENTIATION, SUBCELLULAR LOCATION.
[22]"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.
Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
Tissue: Cervix carcinoma.
[23]"Initial characterization of the human central proteome."
Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.
BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[24]"Solution structure of the first Sam domain of Odin and binding studies with the EphA2 receptor."
Mercurio F.A., Marasco D., Pirone L., Pedone E.M., Pellecchia M., Leone M.
Biochemistry 51:2136-2145(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH ANKS1A.
[25]"The ephrin receptor tyrosine kinase A2 is a cellular receptor for Kaposi's sarcoma-associated herpesvirus."
Hahn A.S., Kaufmann J.K., Wies E., Naschberger E., Panteleev-Ivlev J., Schmidt K., Holzer A., Schmidt M., Chen J., Konig S., Ensser A., Myoung J., Brockmeyer N.H., Sturzl M., Fleckenstein B., Neipel F.
Nat. Med. 18:961-966(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH HHV-8 GLYCOPROTEIN L/GLYCOPROTEIN H.
[26]"Receptor protein tyrosine phosphatase-receptor tyrosine kinase substrate screen identifies EphA2 as a target for LAR in cell migration."
Lee H., Bennett A.M.
Mol. Cell. Biol. 33:1430-1441(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION, PHOSPHORYLATION AT TYR-930, DEPHOSPHORYLATION AT TYR-930 BY PTPRF, INTERACTION WITH NCK1.
[27]"Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors."
Tiwari A., Schneider M., Fiorino A., Haider R., Okoniewski M.J., Roschitzki B., Uzozie A., Menigatti M., Jiricny J., Marra G.
PLoS ONE 8:E69473-E69473(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CEMIP.
[28]"Structures of the cancer-related Aurora-A, FAK, and EphA2 protein kinases from nanovolume crystallography."
Nowakowski J., Cronin C.N., McRee D.E., Knuth M.W., Nelson C.G., Pavletich N.P., Rogers J., Sang B.C., Scheibe D.N., Swanson R.V., Thompson D.A.
Structure 10:1659-1667(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 596-900.
[29]"Solution structure of the C-terminal SAM-domain of EPHAA2: ephrin type-A receptor 2 precursor (EC 2.7.10.1)."
RIKEN structural genomics initiative (RSGI)
Submitted (JAN-2008) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 902-976.
[30]"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 (2.52 ANGSTROMS) OF 28-201, X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 28-201 IN COMPLEX WITH EFNA1, SUBUNIT, DISULFIDE BOND, MUTAGENESIS OF ARG-103.
[31]"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 (1.95 ANGSTROMS) OF 25-202, DISULFIDE BOND.
[32]"Left-handed dimer of EPHA2 transmembrane domain helix packing diversity among receptor tyrosine kinases."
Mayzel M.L., Bocharov E.V., Volynsky P.E., Arseniev A.S.
Submitted (AUG-2009) to the PDB data bank
Cited for: STRUCTURE BY NMR OF 523-563.
[33]"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. expand/collapse author list , 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] ARG-391; MET-511; HIS-568; SER-777 AND HIS-876.
[34]"The EPHA2 gene is associated with cataracts linked to chromosome 1p."
Shiels A., Bennett T.M., Knopf H.L.S., Maraini G., Li A., Jiao X., Hejtmancik J.F.
Mol. Vis. 14:2042-2055(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CTRCT6 TRP-948.
[35]"Mutations of the EPHA2 receptor tyrosine kinase gene cause autosomal dominant congenital cataract."
Zhang T., Hua R., Xiao W., Burdon K.P., Bhattacharya S.S., Craig J.E., Shang D., Zhao X., Mackey D.A., Moore A.T., Luo Y., Zhang J., Zhang X.
Hum. Mutat. 30:E603-E611(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CTRCT6 ILE-940.
[36]"EPHA2 is associated with age-related cortical cataract in mice and humans."
Jun G., Guo H., Klein B.E., Klein R., Wang J.J., Mitchell P., Miao H., Lee K.E., Joshi T., Buck M., Chugha P., Bardenstein D., Klein A.P., Bailey-Wilson J.E., Gong X., Spector T.D., Andrew T., Hammond C.J. expand/collapse author list , Elston R.C., Iyengar S.K., Wang B.
PLoS Genet. 5:E1000584-E1000584(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANT CTRCT6 GLN-721, CHARACTERIZATION OF VARIANT CTRCT6 GLN-721.
[37]"Human cataract mutations in EPHA2 SAM domain alter receptor stability and function."
Park J.E., Son A.I., Hua R., Wang L., Zhang X., Zhou R.
PLoS ONE 7:E36564-E36564(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: CHARACTERIZATION OF VARIANTS CTRCT6 ILE-940 AND CTRCT6 TRP-948.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
M59371 mRNA. Translation: AAA53375.1.
AL451042 Genomic DNA. Translation: CAH71943.1.
CH471167 Genomic DNA. Translation: EAW51769.1.
BC037166 mRNA. Translation: AAH37166.1.
CCDSCCDS169.1.
PIRA36355.
RefSeqNP_004422.2. NM_004431.3.
UniGeneHs.171596.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
1MQBX-ray2.30A/B596-900[»]
2E8NNMR-A902-976[»]
2K9YNMR-A/B523-563[»]
2KSONMR-A908-972[»]
2X10X-ray3.00A27-534[»]
2X11X-ray4.83A27-534[»]
3C8XX-ray1.95A23-202[»]
3CZUX-ray2.65A23-202[»]
3FL7X-ray2.50A23-531[»]
3HEIX-ray2.00A/C/E/G/I/K/M/O28-201[»]
3HPNX-ray2.52A/B/C/D/E/F28-201[»]
3KKAX-ray2.40C/D/E903-971[»]
3MBWX-ray2.81A23-326[»]
3MX0X-ray3.51A/C27-435[»]
3SKJX-ray2.50E/F23-202[»]
4P2KX-ray1.50A590-876[»]
4P2WX-ray2.81A/B590-876[»]
4PDOX-ray2.10A/B590-876[»]
ProteinModelPortalP29317.
SMRP29317. Positions 25-528, 555-970.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid108288. 23 interactions.
DIPDIP-96N.
IntActP29317. 15 interactions.
MINTMINT-3972729.
STRING9606.ENSP00000351209.

Chemistry

BindingDBP29317.
ChEMBLCHEMBL2068.
DrugBankDB01254. Dasatinib.
GuidetoPHARMACOLOGY1822.

PTM databases

PhosphoSiteP29317.

Polymorphism databases

DMDM229462861.

Proteomic databases

MaxQBP29317.
PaxDbP29317.
PRIDEP29317.

Protocols and materials databases

DNASU1969.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000358432; ENSP00000351209; ENSG00000142627.
GeneID1969.
KEGGhsa:1969.
UCSCuc001aya.2. human.

Organism-specific databases

CTD1969.
GeneCardsGC01M016450.
HGNCHGNC:3386. EPHA2.
HPACAB010464.
MIM116600. phenotype.
176946. gene.
neXtProtNX_P29317.
Orphanet98993. Posterior polar cataract.
98994. Total congenital cataract.
PharmGKBPA27818.
GenAtlasSearch...

Phylogenomic databases

eggNOGCOG0515.
HOGENOMHOG000233856.
HOVERGENHBG062180.
InParanoidP29317.
KOK05103.
OMALVPIGQC.
OrthoDBEOG7VTDM6.
PhylomeDBP29317.
TreeFamTF315608.

Enzyme and pathway databases

BRENDA2.7.10.1. 2681.
SignaLinkP29317.

Gene expression databases

ArrayExpressP29317.
BgeeP29317.
CleanExHS_EPHA2.
GenevestigatorP29317.

Family and domain databases

Gene3D1.10.150.50. 1 hit.
2.60.120.260. 1 hit.
2.60.40.10. 2 hits.
InterProIPR027936. Eph_TM.
IPR001090. Ephrin_rcpt_lig-bd_dom.
IPR003961. Fibronectin_type3.
IPR008979. Galactose-bd-like.
IPR009030. Growth_fac_rcpt_N_dom.
IPR013783. Ig-like_fold.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001660. SAM.
IPR013761. SAM/pointed.
IPR021129. SAM_type1.
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]
PfamPF14575. EphA2_TM. 1 hit.
PF01404. Ephrin_lbd. 1 hit.
PF00041. fn3. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
PF00536. SAM_1. 1 hit.
[Graphical view]
PIRSFPIRSF000666. TyrPK_ephrin_receptor. 1 hit.
PRINTSPR00109. TYRKINASE.
SMARTSM00615. EPH_lbd. 1 hit.
SM00060. FN3. 2 hits.
SM00454. SAM. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMSSF47769. SSF47769. 1 hit.
SSF49265. SSF49265. 1 hit.
SSF49785. SSF49785. 1 hit.
SSF56112. SSF56112. 1 hit.
SSF57184. SSF57184. 2 hits.
PROSITEPS51550. 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]
ProtoNetSearch...

Other

EvolutionaryTraceP29317.
GeneWikiEPH_receptor_A2.
GenomeRNAi1969.
NextBio7983.
PROP29317.
SOURCESearch...

Entry information

Entry nameEPHA2_HUMAN
AccessionPrimary (citable) accession number: P29317
Secondary accession number(s): Q8N3Z2
Entry history
Integrated into UniProtKB/Swiss-Prot: December 1, 1992
Last sequence update: May 5, 2009
Last modified: July 9, 2014
This is version 172 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM