Ephrin type-A receptor 8 precursor - Mus musculus (Mouse)

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O09127 (EPHA8_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Last modified May 1, 2013. Version 129. History...

Clusters with 100%, 90%, 50% identity |

Documents (3) |

Third-party data

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Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents Customize order

Names and origin

Protein names

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 names

Name:	Epha8
Synonyms:	Eek

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	1004 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 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 process	Cell adhesion Neurogenesis
Cellular component	Cell membrane Cell projection Endosome Membrane
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein Ubl conjugation
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	axon guidance Inferred from mutant phenotype Ref.3. Source: UniProtKB cell adhesion Inferred from electronic annotation. Source: UniProtKB-KW 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.4 Ref.5. 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_component	early endosome membrane Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from direct assay Ref.1. Source: UniProtKB neuron projection Inferred from direct assay Ref.8. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW GPI-linked ephrin receptor activity Inferred from direct assay Ref.5 Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 26

Potential

Chain

27 – 1004

978

Ephrin type-A receptor 8

PRO_0000016823

Regions

Topological domain

27 – 541

515

Extracellular Potential

Transmembrane

542 – 562

Helical; Potential

Topological domain

563 – 1004

442

Cytoplasmic Potential

Domain

30 – 208

179

Eph LBD

Domain

327 – 429

103

Fibronectin type-III 1

Domain

435 – 530

Fibronectin type-III 2

Domain

634 – 895

262

Protein kinase

Domain

929 – 993

SAM

Nucleotide binding

640 – 648

ATP By similarity

Region

563 – 569

Mediates interaction with ANKS1A and ANKS1B

Region

588 – 643

Mediates interaction with PIK3CG and required for endocytosis

Motif

1002 – 1004

PDZ-binding Potential

Compositional bias

190 – 324

135

Cys-rich

Sites

Active site

759

Proton acceptor By similarity

Binding site

666

ATP By similarity

Amino acid modifications

Modified residue

615

Phosphotyrosine; by autocatalysis Ref.4

Modified residue

838

Phosphotyrosine; by autocatalysis Ref.4

Glycosylation

339

N-linked (GlcNAc...) Potential

Glycosylation

406

N-linked (GlcNAc...) Potential

Glycosylation

431

N-linked (GlcNAc...) Potential

Experimental info

Mutagenesis

615

Y → F: Reduced phosphorylation and reduced association with FYN. Ref.4 Ref.5

Mutagenesis

666

K → M or R: Kinase-dead. Loss of autophosphorylation but has no effect on regulation of cell adhesion. Ref.5

Mutagenesis

792

Y → F: Reduced phosphorylation. Ref.5

Mutagenesis

838

Y → F: Reduced tyrosine kinase activity. Ref.4

Sequence conflict

1000

P → R in AAB39218. Ref.1

Sequences

Sequence

Length

Mass (Da)

Tools

O09127 [UniParc].

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

1,004

110,705

        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' referencesShow '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. 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, AUTOPHOSPHORYLATION 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.
IPI	IPI00263411.
RefSeq	NP_031965.2. NM_007939.2.
UniGene	Mm.1390.
3D structure databases
ProteinModelPortal	O09127.
SMR	O09127. Positions 29-533, 600-899, 925-999.
ModBase	Search...
Protein-protein interaction databases
STRING	10090.ENSMUSP00000030420.
PTM databases
PhosphoSite	O09127.
Proteomic databases
PRIDE	O09127.
Protocols and materials databases
DNASU	13842.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000030420; ENSMUSP00000030420; ENSMUSG00000028661.
GeneID	13842.
KEGG	mmu:13842.
Organism-specific databases
CTD	2046.
MGI	MGI:109378. Epha8.
Phylogenomic databases
eggNOG	COG0515.
GeneTree	ENSGT00700000104300.
HOGENOM	HOG000233856.
HOVERGEN	HBG062180.
InParanoid	A3KG07.
KO	K05109.
OMA	VTTRATV.
OrthoDB	EOG4MCWZJ.
Enzyme and pathway databases
BRENDA	2.7.10.1. 3474.
Gene expression databases
ArrayExpress	O09127.
Bgee	O09127.
CleanEx	MM_EPHA8.
Genevestigator	O09127.
GermOnline	ENSMUSG00000028661. Mus musculus.
Family and domain databases
Gene3D	1.10.150.50. 1 hit. 2.60.40.10. 2 hits.
InterPro	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_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]
PANTHER	PTHR24416:SF23. PTHR24416:SF23. 1 hit.
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. SSF56112. Kinase_like. 1 hit. SSF47769. SAM_homology. 1 hit.
PROSITE	PS01186. EGF_2. 1 hit. Uncertain. 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
NextBio	284680.
SOURCE	Search...

Entry information

Entry name

EPHA8_MOUSE

Accession

Primary (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:	May 1, 2013
This is version 129 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Relevant documents

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

SIMILARITY comments

Index of protein domains and families

Names·Attributes·General annotation·Ontologies·Sequence annotation·Sequences·References·Cross-refs·Entry info·Documents

Preferred order of sections

Names and origin

Protein attributes

General annotation (Comments)

Ontologies

Sequence annotation (Features)

Molecule processing

Regions

Sites

Amino acid modifications

Experimental info

Sequences

References

Cross-references

Sequence databases

3D structure databases

Protein-protein interaction databases

PTM databases

Proteomic databases

Protocols and materials databases

Genome annotation databases

Organism-specific databases

Phylogenomic databases

Enzyme and pathway databases

Gene expression databases

Family and domain databases

Other

Entry information

Relevant documents