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O09127

- EPHA8_MOUSE

UniProt

O09127 - EPHA8_MOUSE

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Protein
Ephrin type-A receptor 8
Gene
Epha8, Eek
Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5 - Experimental evidence at protein leveli

Functioni

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.6 Publications

Catalytic activityi

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

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei666 – 6661ATP By similarity
Active sitei759 – 7591Proton acceptor By similarity

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi640 – 6489ATP By similarity

GO - Molecular functioni

  1. ATP binding Source: UniProtKB-KW
  2. GPI-linked ephrin receptor activity Source: UniProtKB
  3. protein binding Source: UniProtKB

GO - Biological processi

  1. axon guidance Source: UniProtKB
  2. cell adhesion Source: UniProtKB-KW
  3. ephrin receptor signaling pathway Source: UniProtKB
  4. neuron projection development Source: UniProtKB
  5. neuron remodeling Source: UniProtKB
  6. positive regulation of MAPK cascade Source: UniProtKB
  7. positive regulation of phosphatidylinositol 3-kinase activity Source: UniProtKB
  8. protein autophosphorylation Source: UniProtKB
  9. regulation of cell adhesion Source: UniProtKB
  10. regulation of cell adhesion mediated by integrin Source: UniProtKB
  11. substrate-dependent cell migration Source: UniProtKB
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein, Kinase, Receptor, Transferase, Tyrosine-protein kinase

Keywords - Biological processi

Cell adhesion, Neurogenesis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BRENDAi2.7.10.1. 3474.

Names & Taxonomyi

Protein namesi
Recommended 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 namesi
Name:Epha8
Synonyms:Eek
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
ProteomesiUP000000589: Chromosome 4

Organism-specific databases

MGIiMGI:109378. Epha8.

Subcellular locationi

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.4 Publications

Topology

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Topological domaini27 – 541515Extracellular Reviewed prediction
Add
BLAST
Transmembranei542 – 56221Helical; Reviewed prediction
Add
BLAST
Topological domaini563 – 1004442Cytoplasmic Reviewed prediction
Add
BLAST

GO - Cellular componenti

  1. early endosome membrane Source: UniProtKB-SubCell
  2. integral component of plasma membrane Source: UniProtKB
  3. neuron projection Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cell projection, Endosome, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi615 – 6151Y → F: Reduced phosphorylation and reduced association with FYN. 2 Publications
Mutagenesisi666 – 6661K → M or R: Kinase-dead. Loss of autophosphorylation but has no effect on regulation of cell adhesion. 1 Publication
Mutagenesisi792 – 7921Y → F: Reduced phosphorylation. 1 Publication
Mutagenesisi838 – 8381Y → F: Reduced tyrosine kinase activity. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Signal peptidei1 – 2626 Reviewed prediction
Add
BLAST
Chaini27 – 1004978Ephrin type-A receptor 8
PRO_0000016823Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Glycosylationi339 – 3391N-linked (GlcNAc...) Reviewed prediction
Glycosylationi406 – 4061N-linked (GlcNAc...) Reviewed prediction
Glycosylationi431 – 4311N-linked (GlcNAc...) Reviewed prediction
Modified residuei615 – 6151Phosphotyrosine; by autocatalysis1 Publication
Modified residuei838 – 8381Phosphotyrosine; by autocatalysis1 Publication

Post-translational modificationi

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.2 Publications
Ubiquitinated. Ubiquitination by CBL regulates the receptor stability and activity through proteasomal degradation. ANKS1A prevents ubiquitination and degradation.1 Publication

Keywords - PTMi

Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PRIDEiO09127.

PTM databases

PhosphoSiteiO09127.

Expressioni

Tissue specificityi

Specifically expressed in the central nervous system.

Developmental stagei

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.1 Publication

Gene expression databases

BgeeiO09127.
CleanExiMM_EPHA8.
GenevestigatoriO09127.

Interactioni

Subunit structurei

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.6 Publications

Protein-protein interaction databases

IntActiO09127. 1 interaction.
MINTiMINT-5312751.
STRINGi10090.ENSMUSP00000030420.

Structurei

3D structure databases

ProteinModelPortaliO09127.
SMRiO09127. Positions 30-533, 595-900, 925-999.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini30 – 208179Eph LBD
Add
BLAST
Domaini327 – 437111Fibronectin type-III 1
Add
BLAST
Domaini438 – 53396Fibronectin type-III 2
Add
BLAST
Domaini634 – 895262Protein kinase
Add
BLAST
Domaini929 – 99365SAM
Add
BLAST

Region

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Regioni563 – 5697Mediates interaction with ANKS1A and ANKS1B
Regioni588 – 64356Mediates interaction with PIK3CG and required for endocytosis
Add
BLAST

Motif

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Motifi1002 – 10043PDZ-binding Reviewed prediction

Compositional bias

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Compositional biasi190 – 324135Cys-rich
Add
BLAST

Sequence similaritiesi

Keywords - Domaini

Repeat, Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiCOG0515.
GeneTreeiENSGT00750000117255.
HOGENOMiHOG000233856.
HOVERGENiHBG062180.
InParanoidiA3KG07.
KOiK05109.
OMAiVTTRATV.
OrthoDBiEOG7VTDM6.
TreeFamiTF315608.

Family and domain databases

Gene3Di1.10.150.50. 1 hit.
2.60.120.260. 1 hit.
2.60.40.10. 2 hits.
InterProiIPR027936. 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]
PANTHERiPTHR24416:SF274. PTHR24416:SF274. 1 hit.
PfamiPF14575. 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]
PIRSFiPIRSF000666. TyrPK_ephrin_receptor. 1 hit.
PRINTSiPR00109. TYRKINASE.
SMARTiSM00615. EPH_lbd. 1 hit.
SM00060. FN3. 2 hits.
SM00454. SAM. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]
SUPFAMiSSF47769. SSF47769. 1 hit.
SSF49265. SSF49265. 1 hit.
SSF49785. SSF49785. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEiPS01186. 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]

Sequencei

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

O09127-1 [UniParc]FASTAAdd to Basket

« Hide

MAPARARLSP ALWVVTAAAA ATCVSAGRGE VNLLDTSTIH GDWGWLTYPA     50
HGWDSINEVD ESFRPIHTYQ VCNVMSPNQN NWLRTNWVPR DGARRVYAEI 100
KFTLRDCNSI PGVLGTCKET FNLHYLESDR DLGASTQESQ FLKIDTIAAD 150
ESFTGADLGV RRLKLNTEVR GVGPLSKRGF YLAFQDIGAC LAILSLRIYY 200
KKCPAMVRNL AAFSEAVTGA DSSSLVEVRG QCVRHSEERD TPKMYCSAEG 250
EWLVPIGKCV CSAGYEERRD ACMACELGFY KSAPGDQLCA RCPPHSHSAT 300
PAAQTCRCDL SYYRAALDPP SAACTRPPSA PVNLISSVNG TSVTLEWAPP 350
LDPGGRSDIT YNAVCRRCPW ALSHCEACGS GTRFVPQQTS LAQASLLVAN 400
LLAHMNYSFW IEAVNGVSNL SPEPRSAAVV NITTNQAAPS QVVVIRQERA 450
GQTSVSLLWQ EPEQPNGIIL EYEIKYYEKD KEMQSYSTLK AVTTRATVSG 500
LKPGTRYVFQ VRARTSAGCG RFSQAMEVET GKPRPRYDTR TIVWICLTLI 550
TGLVVLLLLL ICKKRHCGYS KAFQDSDEEK MHYQNGQAPP PVFLPLNHPP 600
GKFPETQFSA EPHTYEEPGR AGRSFTREIE ASRIHIEKII GSGESGEVCY 650
GRLQVPGQRD VPVAIKALKA GYTERQRQDF LSEAAIMGQF DHPNIIRLEG 700
VVTRGRLAMI VTEYMENGSL DAFLRTHDGQ FTIVQLVGML RGVGAGMRYL 750
SDLGYIHRDL AARNVLVDGR LVCKVSDFGL SRALEDDPEA AYTTAGGKIP 800
IRWTAPEAIA FRTFSSASDV WSFGVVMWEV LAYGERPYWN MTNQDVISSV 850
EEGYRLPAPM GCPRALHQLM LDCWHKDRAQ RPRFAHVVSV LDALVHSPES 900
LRATATVSRC PPPAFARSCF DLRAGGSGNG DLTVGDWLDS IRMGRYRDHF 950
AAGGYSSLGM VLRMNAQDVR ALGITLMGHQ KKILGSIQTM RAQLSSTQGP 1000
RRHL 1004
Length:1,004
Mass (Da):110,705
Last modified:July 27, 2011 - v2
Checksum:i8530E8002A6FE502
GO

Sequence conflict

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Sequence conflicti1000 – 10001P → R in AAB39218. 1 Publication

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U72207 mRNA. Translation: AAB39218.1.
AL627214 Genomic DNA. Translation: CAM46147.1.
CCDSiCCDS18813.1.
RefSeqiNP_031965.2. NM_007939.2.
UniGeneiMm.1390.

Genome annotation databases

EnsembliENSMUST00000030420; ENSMUSP00000030420; ENSMUSG00000028661.
GeneIDi13842.
KEGGimmu:13842.
UCSCiuc008vis.1. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBL
GenBank
DDBJ
Links Updated
U72207 mRNA. Translation: AAB39218.1 .
AL627214 Genomic DNA. Translation: CAM46147.1 .
CCDSi CCDS18813.1.
RefSeqi NP_031965.2. NM_007939.2.
UniGenei Mm.1390.

3D structure databases

ProteinModelPortali O09127.
SMRi O09127. Positions 30-533, 595-900, 925-999.
ModBasei Search...
MobiDBi Search...

Protein-protein interaction databases

IntActi O09127. 1 interaction.
MINTi MINT-5312751.
STRINGi 10090.ENSMUSP00000030420.

PTM databases

PhosphoSitei O09127.

Proteomic databases

PRIDEi O09127.

Protocols and materials databases

DNASUi 13842.
Structural Biology Knowledgebase Search...

Genome annotation databases

Ensembli ENSMUST00000030420 ; ENSMUSP00000030420 ; ENSMUSG00000028661 .
GeneIDi 13842.
KEGGi mmu:13842.
UCSCi uc008vis.1. mouse.

Organism-specific databases

CTDi 2046.
MGIi MGI:109378. Epha8.

Phylogenomic databases

eggNOGi COG0515.
GeneTreei ENSGT00750000117255.
HOGENOMi HOG000233856.
HOVERGENi HBG062180.
InParanoidi A3KG07.
KOi K05109.
OMAi VTTRATV.
OrthoDBi EOG7VTDM6.
TreeFami TF315608.

Enzyme and pathway databases

BRENDAi 2.7.10.1. 3474.

Miscellaneous databases

NextBioi 284680.
PROi O09127.
SOURCEi Search...

Gene expression databases

Bgeei O09127.
CleanExi MM_EPHA8.
Genevestigatori O09127.

Family and domain databases

Gene3Di 1.10.150.50. 1 hit.
2.60.120.260. 1 hit.
2.60.40.10. 2 hits.
InterProi IPR027936. 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 ]
PANTHERi PTHR24416:SF274. PTHR24416:SF274. 1 hit.
Pfami PF14575. 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 ]
PIRSFi PIRSF000666. TyrPK_ephrin_receptor. 1 hit.
PRINTSi PR00109. TYRKINASE.
SMARTi SM00615. EPH_lbd. 1 hit.
SM00060. FN3. 2 hits.
SM00454. SAM. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view ]
SUPFAMi SSF47769. SSF47769. 1 hit.
SSF49265. SSF49265. 1 hit.
SSF49785. SSF49785. 1 hit.
SSF56112. SSF56112. 1 hit.
PROSITEi PS01186. 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 ]
ProtoNeti Search...

Publicationsi

« Hide 'large scale' publications
  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. 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.

Entry informationi

Entry nameiEPHA8_MOUSE
AccessioniPrimary (citable) accession number: O09127
Secondary accession number(s): A3KG07
Entry historyi
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 statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  3. SIMILARITY comments
    Index of protein domains and families

External Data

Dasty 3

Similar proteinsi