P29317 (EPHA2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

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	976 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 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
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. Interacts with ANKS1A 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. Ref.6 Ref.8 Ref.9 Ref.11 Ref.20 Ref.26
Subcellular location	Cell membrane; Single-pass type I membrane protein. Cell projection › ruffle membrane; Single-pass type I membrane protein. Cell projection › lamellipodium membrane; Single-pass type I membrane protein. Cell junction › focal 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 By similarity. 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 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, cortical, age-related, 2 (ARCC2) [MIM:613020]: A developmental punctate opacity restricted to the cortex. The cataract is white or cerulean, increases in number with age, but rarely affects vision. Note: Disease susceptibility is associated with variations affecting the gene represented in this entry. Ref.16 Ref.32 Cataract, posterior polar, 1 (CTPP1) [MIM:116600]: A subcapsular opacity, usually disk-shaped, located at the back of the lens. It can have a marked effect on visual acuity. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.16 Ref.30 Ref.31 Ref.33 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 process	Angiogenesis Apoptosis Cell adhesion Differentiation
Cellular component	Cell junction Cell membrane Cell projection Membrane
Coding sequence diversity	Polymorphism
Disease	Cataract Disease mutation
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	activation of Rac GTPase activity Inferred from mutant phenotype Ref.20. Source: UniProtKB angiogenesis Inferred from electronic annotation. Source: UniProtKB-KW apoptotic process Inferred from direct assay Ref.12. Source: UniProtKB axial mesoderm formation Inferred from electronic annotation. Source: Compara 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 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 negative regulation of protein kinase B signaling cascade Inferred from direct assay Ref.16. Source: UniProtKB neural tube development Inferred from electronic annotation. Source: Compara neuron differentiation Inferred from electronic annotation. Source: Compara notochord cell development Inferred from electronic annotation. Source: Compara notochord formation Inferred from electronic annotation. Source: Compara osteoblast differentiation Inferred from sequence or structural similarity. Source: UniProtKB osteoclast differentiation Inferred from sequence or structural similarity. Source: UniProtKB 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: Compara protein kinase B signaling cascade 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 stimulus Inferred from mutant phenotype Ref.16. Source: UniProtKB skeletal system development Inferred from electronic annotation. Source: Compara vasculogenesis Inferred from electronic annotation. Source: Compara
Cellular_component	focal adhesion Inferred from direct assay Ref.6. Source: UniProtKB integral to 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 ruffle membrane Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW ephrin receptor activity Inferred from electronic annotation. Source: InterPro transmembrane receptor protein tyrosine kinase activity Inferred from direct assay Ref.6. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
EFNA1	P20827	5	EBI-702104,EBI-715194
EPHA7	Q15375	3	EBI-702104,EBI-1383428
HSP90AB1	P08238	2	EBI-702104,EBI-352572
PTK2	Q05397	3	EBI-702104,EBI-702142

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 23

23

Potential

Chain

24 – 976

953

Ephrin type-A receptor 2

PRO_0000016800

Regions

Topological domain

24 – 537

514

Extracellular Potential

Transmembrane

538 – 558

21

Helical; Potential

Topological domain

559 – 976

418

Cytoplasmic Potential

Domain

28 – 206

179

Eph LBD

Domain

328 – 429

102

Fibronectin type-III 1

Domain

435 – 526

92

Fibronectin type-III 2

Domain

613 – 875

263

Protein kinase

Domain

904 – 968

65

SAM

Nucleotide binding

619 – 627

9

ATP By similarity

Region

1 – 206

206

Mediates interaction with CLDN4

Region

606 – 906

301

Mediates interaction with ARHGEF16 and ELMO2

Region

886 – 976

91

Negatively regulates interaction with ARHGEF16

Motif

974 – 976

3

PDZ-binding Potential

Compositional bias

188 – 325

138

Cys-rich

Sites

Active site

739

1

Proton acceptor By similarity

Binding site

646

1

ATP By similarity

Amino acid modifications

Modified residue

153

1

Phosphoserine

Modified residue

373

1

Phosphoserine

Modified residue

570

1

Phosphoserine Ref.13 Ref.15 Ref.19

Modified residue

575

1

Phosphotyrosine

Modified residue

579

1

Phosphoserine Ref.13

Modified residue

587

1

Phosphothreonine

Modified residue

588

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

593

1

Phosphothreonine

Modified residue

594

1

Phosphotyrosine; by autocatalysis

Modified residue

628

1

Phosphotyrosine Ref.19

Modified residue

647

1

Phosphothreonine Ref.13 Ref.19

Modified residue

735

1

Phosphotyrosine; by autocatalysis By similarity

Modified residue

771

1

Phosphothreonine

Modified residue

772

1

Phosphotyrosine; by autocatalysis

Modified residue

790

1

Phosphoserine

Modified residue

791

1

Phosphotyrosine

Modified residue

869

1

Phosphoserine Ref.19

Modified residue

880

1

Phosphoserine

Modified residue

892

1

Phosphoserine Ref.15

Modified residue

897

1

Phosphoserine; by PKB Ref.16

Modified residue

898

1

Phosphothreonine

Modified residue

899

1

Phosphoserine

Modified residue

901

1

Phosphoserine Ref.15

Modified residue

910

1

Phosphoserine

Modified residue

921

1

Phosphotyrosine; by autocatalysis Potential

Modified residue

930

1

Phosphotyrosine

Modified residue

960

1

Phosphotyrosine

Glycosylation

407

1

N-linked (GlcNAc...) Potential

Glycosylation

435

1

N-linked (GlcNAc...) Ref.17

Disulfide bond

70 ↔ 188

Ref.26 Ref.27

Disulfide bond

105 ↔ 115

Ref.26 Ref.27

Natural variations

Natural variant

99

1

K → N.
Corresponds to variant rs1058372 [ dbSNP | Ensembl ].

VAR_055989

Natural variant

391

1

G → R. Ref.29
Corresponds to variant rs34192549 [ dbSNP | Ensembl ].

VAR_042121

Natural variant

511

1

T → M. Ref.29
Corresponds to variant rs55747232 [ dbSNP | Ensembl ].

VAR_042122

Natural variant

568

1

R → H. Ref.29
Corresponds to variant rs56198600 [ dbSNP | Ensembl ].

VAR_042123

Natural variant

631

1

M → T.
Corresponds to variant rs34021505 [ dbSNP | Ensembl ].

VAR_055990

Natural variant

721

1

R → Q in ARCC2; retained in the cytoplasm and constitutively active it alters EPHA2 signaling. Ref.32

VAR_062532

Natural variant

777

1

G → S in a gastric adenocarcinoma sample; somatic mutation. Ref.29

VAR_042124

Natural variant

876

1

R → H. Ref.29
Corresponds to variant rs35903225 [ dbSNP | Ensembl ].

VAR_042125

Natural variant

940

1

T → I in CTPP1; reduced protein stability and reduced ability to stimulate cell migration in absence of its ephrin ligand. Ref.31 Ref.33

VAR_058907

Natural variant

948

1

G → W in CTPP1; reduced protein stability and reduced ability to stimulate cell migration in absence of its ephrin ligand. Ref.30 Ref.33

VAR_058908

Experimental info

Mutagenesis

103

1

R → E: Significantly reduced response to EFNA1. Ref.26

Mutagenesis

646

1

K → M: Loss of kinase activity. Ref.9

Mutagenesis

739

1

D → N: Increases serum-induced chemotaxis. Loss of EFNA1-dependent regulation of cell migration. Ref.16

Mutagenesis

897

1

S → A or D: Loss of serum-induced phosphorylation by PKB. Loss of serum-induced chemotaxis. Ref.16

Sequence conflict

94 – 99

6

IFIELK → NNFELN in AAA53375. Ref.1

Secondary structure

1

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976

Helix Strand Turn

Details...

Beta strand

28 – 33

6

Helix

34 – 36

3

Turn

37 – 40

4

Beta strand

44 – 57

14

Beta strand

59 – 62

4

Beta strand

64 – 69

6

Beta strand

73 – 76

4

Beta strand

79 – 82

4

Beta strand

92 – 103

12

Helix

105 – 107

3

Beta strand

108 – 110

3

Turn

112 – 114

3

Beta strand

119 – 128

10

Helix

136 – 138

3

Beta strand

139 – 145

7

Beta strand

148 – 151

4

Helix

153 – 157

5

Beta strand

161 – 170

10

Beta strand

175 – 187

13

Beta strand

189 – 199

11

Beta strand

204 – 206

3

Beta strand

209 – 211

3

Beta strand

218 – 221

4

Beta strand

224 – 227

4

Beta strand

238 – 240

3

Beta strand

244 – 247

4

Beta strand

253 – 257

5

Beta strand

266 – 269

4

Beta strand

272 – 275

4

Beta strand

286 – 288

3

Beta strand

295 – 298

4

Beta strand

335 – 338

4

Beta strand

343 – 348

6

Beta strand

361 – 369

9

Beta strand

376 – 378

3

Beta strand

384 – 387

4

Beta strand

389 – 392

4

Beta strand

394 – 400

7

Beta strand

407 – 415

9

Helix

419 – 421

3

Beta strand

427 – 433

7

Beta strand

441 – 446

6

Beta strand

453 – 457

5

Turn

460 – 465

6

Beta strand

467 – 475

9

Beta strand

483 – 493

11

Beta strand

502 – 510

9

Beta strand

522 – 525

4

Helix

536 – 556

21

Beta strand

557 – 561

5

Turn

610 – 612

3

Beta strand

613 – 621

9

Beta strand

623 – 633

11

Beta strand

640 – 648

9

Helix

654 – 668

15

Beta strand

678 – 682

5

Beta strand

684 – 693

10

Helix

700 – 706

7

Turn

707 – 709

3

Helix

713 – 732

20

Helix

742 – 744

3

Beta strand

745 – 747

3

Beta strand

753 – 755

3

Helix

781 – 783

3

Helix

786 – 790

5

Helix

796 – 811

16

Turn

817 – 820

4

Helix

823 – 831

9

Helix

844 – 853

10

Turn

858 – 860

3

Helix

864 – 876

13

Helix

878 – 882

5

Helix

909 – 915

7

Helix

919 – 921

3

Helix

922 – 927

6

Helix

933 – 937

5

Helix

941 – 946

6

Helix

952 – 964

13

Sequences

	Sequence		Length	Mass (Da)
	P29317 [UniParc]. Last modified May 5, 2009. Version 2. Checksum: 845D7E1BBCCAACCC	FASTA	976	108,266
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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, MASS SPECTROMETRY. 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, MASS SPECTROMETRY. 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, MASS SPECTROMETRY. 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, MASS SPECTROMETRY.
[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]	"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.
[25]	"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.
[26]	"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.
[27]	"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.
[28]	"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.
[29]	"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] ARG-391; MET-511; HIS-568; SER-777 AND HIS-876.
[30]	"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 CTPP1 TRP-948, INVOLVEMENT IN AGE-RELATED CATARACTS.
[31]	"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 CTPP1 ILE-940.
[32]	"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. , Elston R.C., Iyengar S.K., Wang B. PLoS Genet. 5:E1000584-E1000584(2009) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT ARCC2 GLN-721, CHARACTERIZATION OF VARIANT ARCC2 GLN-721.
[33]	"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 CTPP1 ILE-940 AND CTPP1 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.

IPI

IPI00021267.

PIR

A36355.

RefSeq

NP_004422.2. NM_004431.3.

UniGene

Hs.171596.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1MQB	X-ray	2.30	A/B	596-900	[»]
2E8N	NMR	-	A	902-976	[»]
2K9Y	NMR	-	A/B	523-563	[»]
2KSO	NMR	-	A	908-972	[»]
2X10	X-ray	3.00	A	27-534	[»]
2X11	X-ray	4.83	A	27-534	[»]
3C8X	X-ray	1.95	A	23-202	[»]
3CZU	X-ray	2.65	A	23-202	[»]
3FL7	X-ray	2.50	A	23-531	[»]
3HEI	X-ray	2.00	A/C/E/G/I/K/M/O	28-201	[»]
3HPN	X-ray	2.52	A/B/C/D/E/F	28-201	[»]
3KKA	X-ray	2.40	C/D/E	903-971	[»]
3MBW	X-ray	2.81	A	23-326	[»]
3MX0	X-ray	3.51	A/C	27-435	[»]
3SKJ	X-ray	2.50	E/F	23-202	[»]

ProteinModelPortal

P29317.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-96N.

IntAct

P29317. 14 interactions.

MINT

MINT-3972729.

STRING

9606.ENSP00000351209.

PTM databases

PhosphoSite

P29317.

Polymorphism databases

DMDM

229462861.

Proteomic databases

PaxDb

P29317.

PRIDE

P29317.

Protocols and materials databases

DNASU

1969.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000358432; ENSP00000351209; ENSG00000142627.

GeneID

1969.

KEGG

hsa:1969.

UCSC

uc001aya.2. human.

Organism-specific databases

CTD

1969.

GeneCards

GC01M016450.

HGNC

HGNC:3386. EPHA2.

HPA

CAB010464.

MIM

116600. phenotype.
176946. gene.
613020. phenotype.

neXtProt

NX_P29317.

Orphanet

98993. Posterior polar cataract.
98994. Total congenital cataract.

PharmGKB

PA27818.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233856.

HOVERGEN

HBG062180.

InParanoid

P29317.

KO

K05103.

OMA

LVPIGQC.

OrthoDB

EOG4Q84WS.

PhylomeDB

P29317.

Enzyme and pathway databases

BRENDA

2.7.10.1. 2681.

Pathway_Interaction_DB

epha_fwdpathway. EPHA forward signaling.
epha2_fwdpathway. EPHA2 forward signaling.
ephrina_ephapathway. EphrinA-EPHA pathway.

Gene expression databases

ArrayExpress

P29317.

Bgee

P29317.

CleanEx

HS_EPHA2.

Genevestigator

P29317.

GermOnline

ENSG00000142627. 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.
IPR009030. Growth_fac_rcpt.
IPR013783. Ig-like_fold.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_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]

Pfam

PF01404. Ephrin_lbd. 1 hit.
PF00041. fn3. 2 hits.
PF07714. Pkinase_Tyr. 1 hit.
PF00536. SAM_1. 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.
SSF57184. Grow_fac_recept. 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

P29317.

ChEMBL

CHEMBL2068.

DrugBank

DB01254. Dasatinib.

EvolutionaryTrace

P29317.

GenomeRNAi

1969.

NextBio

7983.

SOURCE

Search...

Entry information

Entry name

EPHA2_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 158 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.