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O09127 (EPHA8_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 142. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (3) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
Ephrin type-A receptor 8

EC=2.7.10.1
Alternative name(s):
EPH- and ELK-related kinase
Tyrosine-protein kinase receptor EEK
Gene names
Name:Epha8
Synonyms:Eek
OrganismMus musculus (Mouse) [Reference proteome]
Taxonomic identifier10090 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus

Protein attributes

Sequence length1004 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 GPI-anchored 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. The GPI-anchored ephrin-A EFNA2, EFNA3, and EFNA5 are able to activate EPHA8 through phosphorylation. With EFNA5 may regulate integrin-mediated cell adhesion and migration on fibronectin substrate but also neurite outgrowth. During development of the nervous system plays also a role in axon guidance. Downstream effectors of the EPHA8 signaling pathway include FYN which promotes cell adhesion upon activation by EPHA8 and the MAP kinases in the stimulation of neurite outgrowth. Ref.3 Ref.4 Ref.5 Ref.6 Ref.7 Ref.8

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 By similarity. May also form heterodimers with other ephrin receptors. Interacts with FYN; possible downstream effector of EPHA8 in regulation of cell adhesion. Interacts with PIK3CG; regulates integrin-mediated cell adhesion to substrate. Interacts with TIAM1; regulates clathrin-mediated endocytosis of EPHA8. Interacts with ANKS1A and ANKS1B; EPHA8 kinase activity-independent but stimulated by EPHA8 ubiquitination. Ref.1 Ref.4 Ref.5 Ref.8 Ref.9 Ref.10

Subcellular location

Cell membrane; Single-pass type I membrane protein. Cell projection. Early endosome membrane. Note: Undergoes clathrin-mediated endocytosis upon EFNA5-binding and is targeted to early endosomes. Ref.1 Ref.7 Ref.8 Ref.10

Tissue specificity

Specifically expressed in the central nervous system.

Developmental stage

First detected at E10.5 with high levels near the midline region of the tectum and to a lower extent in discrete regions of hindbrain, the dorsal horn, of the spinal cord and in the naso-lacrimal groove. The expression decreases at E12.5 and is barely detectable at E17.5. Not detected at postnatal stages. Ref.3

Post-translational modification

Phosphorylated. Phosphorylation is stimulated upon binding of its ligands including EFNA2, EFNA3 and EFNA5. Autophosphorylation on Tyr-615 is critical for association with FYN. Autophosphorylation on Tyr-838 modulates tyrosine kinase activity. Ref.1 Ref.4

Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation. ANKS1A prevents ubiquitination and degradation. Ref.9

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 processCell adhesion
Neurogenesis
   Cellular componentCell membrane
Cell projection
Endosome
Membrane
   DomainRepeat
Signal
Transmembrane
Transmembrane helix
   LigandATP-binding
Nucleotide-binding
   Molecular functionDevelopmental protein
Kinase
Receptor
Transferase
Tyrosine-protein kinase
   PTMGlycoprotein
Phosphoprotein
Ubl conjugation
   Technical termComplete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processaxon guidance

Inferred from mutant phenotype Ref.3. Source: UniProtKB

cell adhesion

Inferred from electronic annotation. Source: UniProtKB-KW

ephrin receptor signaling pathway

Inferred from direct assay Ref.5Ref.8Ref.1. Source: UniProtKB

neuron projection development

Inferred from direct assay Ref.7. Source: UniProtKB

neuron remodeling

Inferred from direct assay Ref.8. Source: UniProtKB

positive regulation of MAPK cascade

Inferred from direct assay Ref.7. Source: UniProtKB

positive regulation of phosphatidylinositol 3-kinase activity

Inferred from direct assay Ref.5. Source: UniProtKB

protein autophosphorylation

Inferred from direct assay Ref.4Ref.5. Source: UniProtKB

regulation of cell adhesion

Inferred from direct assay Ref.4. Source: UniProtKB

regulation of cell adhesion mediated by integrin

Inferred from direct assay Ref.5. Source: UniProtKB

substrate-dependent cell migration

Inferred from direct assay Ref.8. Source: UniProtKB

   Cellular_componentearly endosome membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

integral component of plasma membrane

Inferred from direct assay Ref.1. Source: UniProtKB

neuron projection

Inferred from direct assay Ref.8. Source: UniProtKB

   Molecular_functionATP binding

Inferred from electronic annotation. Source: UniProtKB-KW

GPI-linked ephrin receptor activity

Inferred from direct assay Ref.5Ref.1. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.4Ref.5Ref.8Ref.1. Source: UniProtKB

Complete GO annotation...

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Signal peptide1 – 2626 Potential
Chain27 – 1004978Ephrin type-A receptor 8
PRO_0000016823

Regions

Topological domain27 – 541515Extracellular Potential
Transmembrane542 – 56221Helical; Potential
Topological domain563 – 1004442Cytoplasmic Potential
Domain30 – 208179Eph LBD
Domain327 – 437111Fibronectin type-III 1
Domain438 – 53396Fibronectin type-III 2
Domain634 – 895262Protein kinase
Domain929 – 99365SAM
Nucleotide binding640 – 6489ATP By similarity
Region563 – 5697Mediates interaction with ANKS1A and ANKS1B
Region588 – 64356Mediates interaction with PIK3CG and required for endocytosis
Motif1002 – 10043PDZ-binding Potential
Compositional bias190 – 324135Cys-rich

Sites

Active site7591Proton acceptor By similarity
Binding site6661ATP By similarity

Amino acid modifications

Modified residue6151Phosphotyrosine; by autocatalysis Ref.4
Modified residue8381Phosphotyrosine; by autocatalysis Ref.4
Glycosylation3391N-linked (GlcNAc...) Potential
Glycosylation4061N-linked (GlcNAc...) Potential
Glycosylation4311N-linked (GlcNAc...) Potential

Experimental info

Mutagenesis6151Y → F: Reduced phosphorylation and reduced association with FYN. Ref.4 Ref.5
Mutagenesis6661K → M or R: Kinase-dead. Loss of autophosphorylation but has no effect on regulation of cell adhesion. Ref.5
Mutagenesis7921Y → F: Reduced phosphorylation. Ref.5
Mutagenesis8381Y → F: Reduced tyrosine kinase activity. Ref.4
Sequence conflict10001P → R in AAB39218. Ref.1

Sequences

Sequence LengthMass (Da)Tools
O09127 [UniParc].

Last modified July 27, 2011. Version 2.
Checksum: 8530E8002A6FE502

FASTA1,004110,705
        10         20         30         40         50         60 
MAPARARLSP ALWVVTAAAA ATCVSAGRGE VNLLDTSTIH GDWGWLTYPA HGWDSINEVD 

        70         80         90        100        110        120 
ESFRPIHTYQ VCNVMSPNQN NWLRTNWVPR DGARRVYAEI KFTLRDCNSI PGVLGTCKET 

       130        140        150        160        170        180 
FNLHYLESDR DLGASTQESQ FLKIDTIAAD ESFTGADLGV RRLKLNTEVR GVGPLSKRGF 

       190        200        210        220        230        240 
YLAFQDIGAC LAILSLRIYY KKCPAMVRNL AAFSEAVTGA DSSSLVEVRG QCVRHSEERD 

       250        260        270        280        290        300 
TPKMYCSAEG EWLVPIGKCV CSAGYEERRD ACMACELGFY KSAPGDQLCA RCPPHSHSAT 

       310        320        330        340        350        360 
PAAQTCRCDL SYYRAALDPP SAACTRPPSA PVNLISSVNG TSVTLEWAPP LDPGGRSDIT 

       370        380        390        400        410        420 
YNAVCRRCPW ALSHCEACGS GTRFVPQQTS LAQASLLVAN LLAHMNYSFW IEAVNGVSNL 

       430        440        450        460        470        480 
SPEPRSAAVV NITTNQAAPS QVVVIRQERA GQTSVSLLWQ EPEQPNGIIL EYEIKYYEKD 

       490        500        510        520        530        540 
KEMQSYSTLK AVTTRATVSG LKPGTRYVFQ VRARTSAGCG RFSQAMEVET GKPRPRYDTR 

       550        560        570        580        590        600 
TIVWICLTLI TGLVVLLLLL ICKKRHCGYS KAFQDSDEEK MHYQNGQAPP PVFLPLNHPP 

       610        620        630        640        650        660 
GKFPETQFSA EPHTYEEPGR AGRSFTREIE ASRIHIEKII GSGESGEVCY GRLQVPGQRD 

       670        680        690        700        710        720 
VPVAIKALKA GYTERQRQDF LSEAAIMGQF DHPNIIRLEG VVTRGRLAMI VTEYMENGSL 

       730        740        750        760        770        780 
DAFLRTHDGQ FTIVQLVGML RGVGAGMRYL SDLGYIHRDL AARNVLVDGR LVCKVSDFGL 

       790        800        810        820        830        840 
SRALEDDPEA AYTTAGGKIP IRWTAPEAIA FRTFSSASDV WSFGVVMWEV LAYGERPYWN 

       850        860        870        880        890        900 
MTNQDVISSV EEGYRLPAPM GCPRALHQLM LDCWHKDRAQ RPRFAHVVSV LDALVHSPES 

       910        920        930        940        950        960 
LRATATVSRC PPPAFARSCF DLRAGGSGNG DLTVGDWLDS IRMGRYRDHF AAGGYSSLGM 

       970        980        990       1000 
VLRMNAQDVR ALGITLMGHQ KKILGSIQTM RAQLSSTQGP RRHL 

« Hide

References

« Hide 'large scale' references
[1]"The Eek receptor, a member of the Eph family of tyrosine protein kinases, can be activated by three different Eph family ligands."
Park S., Sanchez M.P.
Oncogene 14:533-542(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH EFNA2; EFNA3 AND EFNA5, PHOSPHORYLATION, TOPOLOGY, SUBCELLULAR LOCATION.
[2]"Lineage-specific biology revealed by a finished genome assembly of the mouse."
Church D.M., Goodstadt L., Hillier L.W., Zody M.C., Goldstein S., She X., Bult C.J., Agarwala R., Cherry J.L., DiCuccio M., Hlavina W., Kapustin Y., Meric P., Maglott D., Birtle Z., Marques A.C., Graves T., Zhou S. expand/collapse author list , Teague B., Potamousis K., Churas C., Place M., Herschleb J., Runnheim R., Forrest D., Amos-Landgraf J., Schwartz D.C., Cheng Z., Lindblad-Toh K., Eichler E.E., Ponting C.P.
PLoS Biol. 7:E1000112-E1000112(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
Strain: C57BL/6J.
[3]"Aberrant axonal projections in mice lacking EphA8 (Eek) tyrosine protein kinase receptors."
Park S., Frisen J., Barbacid M.
EMBO J. 16:3106-3114(1997) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN AXON GUIDANCE, DEVELOPMENTAL STAGE.
[4]"Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity."
Choi S., Park S.
Oncogene 18:5413-5422(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL ADHESION, INTERACTION WITH FYN, PHOSPHORYLATION AT TYR-615 AND TYR-838, MUTAGENESIS OF TYR-615 AND TYR-838.
[5]"The EphA8 receptor regulates integrin activity through p110gamma phosphatidylinositol-3 kinase in a tyrosine kinase activity-independent manner."
Gu C., Park S.
Mol. Cell. Biol. 21:4579-4597(2001) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN INTEGRIN-MEDIATED CELL ADHESION, MUTAGENESIS OF TYR-615; LYS-666 AND TYR-792, INTERACTION WITH PIK3CG.
[6]"The p110 gamma PI-3 kinase is required for EphA8-stimulated cell migration."
Gu C., Park S.
FEBS Lett. 540:65-70(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION.
[7]"The EphA8 receptor induces sustained MAP kinase activation to promote neurite outgrowth in neuronal cells."
Gu C., Shim S., Shin J., Kim J., Park J., Han K., Park S.
Oncogene 24:4243-4256(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN MAP KINASE ACTIVATION AND NEURITE OUTGROWTH, SUBCELLULAR LOCATION.
[8]"Identification of phosphotyrosine binding domain-containing proteins as novel downstream targets of the EphA8 signaling function."
Shin J., Gu C., Park E., Park S.
Mol. Cell. Biol. 27:8113-8126(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION IN CELL MIGRATION AND NEURITE RETRACTION, INTERACTION WITH ANKS1A AND ANKS1B, SUBCELLULAR LOCATION.
[9]"The SAM domains of Anks family proteins are critically involved in modulating the degradation of EphA receptors."
Kim J., Lee H., Kim Y., Yoo S., Park E., Park S.
Mol. Cell. Biol. 30:1582-1592(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: UBIQUITINATION BY CBL, INTERACTION WITH ANKS1A.
[10]"EphA8-ephrinA5 signaling and clathrin-mediated endocytosis is regulated by Tiam-1, a Rac-specific guanine nucleotide exchange factor."
Yoo S., Shin J., Park S.
Mol. Cells 29:603-609(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, INTERACTION WITH TIAM1.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
U72207 mRNA. Translation: AAB39218.1.
AL627214 Genomic DNA. Translation: CAM46147.1.
CCDSCCDS18813.1.
RefSeqNP_031965.2. NM_007939.2.
UniGeneMm.1390.

3D structure databases

ProteinModelPortalO09127.
SMRO09127. Positions 30-533, 595-900, 925-999.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

IntActO09127. 1 interaction.
MINTMINT-5312751.
STRING10090.ENSMUSP00000030420.

PTM databases

PhosphoSiteO09127.

Proteomic databases

PRIDEO09127.

Protocols and materials databases

DNASU13842.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENSMUST00000030420; ENSMUSP00000030420; ENSMUSG00000028661.
GeneID13842.
KEGGmmu:13842.
UCSCuc008vis.1. mouse.

Organism-specific databases

CTD2046.
MGIMGI:109378. Epha8.

Phylogenomic databases

eggNOGCOG0515.
GeneTreeENSGT00750000117255.
HOGENOMHOG000233856.
HOVERGENHBG062180.
InParanoidA3KG07.
KOK05109.
OMAVTTRATV.
OrthoDBEOG7VTDM6.
TreeFamTF315608.

Enzyme and pathway databases

BRENDA2.7.10.1. 3474.

Gene expression databases

BgeeO09127.
CleanExMM_EPHA8.
GenevestigatorO09127.

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.
IPR020691. EphrinA_rcpt8.
IPR003961. Fibronectin_type3.
IPR008979. Galactose-bd-like.
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]
PANTHERPTHR24416:SF274. PTHR24416:SF274. 1 hit.
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.
PROSITEPS01186. EGF_2. 1 hit.
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]
ProtoNetSearch...

Other

NextBio284680.
PROO09127.
SOURCESearch...

Entry information

Entry nameEPHA8_MOUSE
AccessionPrimary (citable) accession number: O09127
Secondary accession number(s): A3KG07
Entry history
Integrated into UniProtKB/Swiss-Prot: November 1, 1997
Last sequence update: July 27, 2011
Last modified: July 9, 2014
This is version 142 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Relevant documents

SIMILARITY comments

Index of protein domains and families

Human and mouse protein kinases

Human and mouse protein kinases: classification and index

MGD cross-references

Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot