P29319 (EPHA3_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ephrin type-A receptor 3
EC=2.7.10.1

Alternative name(s):
EPH-like kinase 4
Short name=EK4
Short name=mEK4
Tyrosine-protein kinase TYRO4
Tyrosine-protein kinase receptor ETK1

Gene names

Name:	Epha3
Synonyms:	Etk1, Mek4, Tyro4

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	983 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 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. Highly promiscuous for ephrin-A ligands it binds preferentially EFNA5. Upon activation by EFNA5 regulates cell-cell adhesion, cytoskeletal organization and cell migration. Plays a role in cardiac cells migration and differentiation and regulates the formation of the atrioventricular canal and septum during development probably through activation by EFNA1. Involved in the retinotectal mapping of neurons. May also control the segregation but not the guidance of motor and sensory axons during neuromuscular circuit development. Ref.5 Ref.6 Ref.7
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. Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function. Interacts (phosphorylated) with PTPN1; dephosphorylates EPHA3 and may regulate its trafficking and function By similarity. Interacts (phosphorylated) with CRK; mediates EFNA5-EPHA3 signaling through RHOA GTPase activation. Interacts with NCK1 (via SH2 domain); mediates EFNA5-EPHA3 signaling. Ref.2 Ref.7
Subcellular location	Isoform Long: Cell membrane; Single-pass type I membrane protein. Isoform Short: Secreted.
Tissue specificity	Greatest levels of expression occurring in the brain, also detected in testis.
Developmental stage	Specifically expressed in heart during its development by mesenchymal cells of the endocardial cushions. Expressed in motor neurons at E11.5. Ref.3 Ref.5
Post-translational modification	Autophosphorylates upon activation by EFNA5. Phosphorylation on Tyr-602 mediates interaction with NCK1. Dephosphorylated by PTPN1 By similarity.
Disruption phenotype	Mice die perinatally due to cardiac failure. Ref.3 Ref.5
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
Cellular component	Cell membrane Membrane Secreted
Coding sequence diversity	Alternative splicing
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic process Inferred from mutant phenotype Ref.5. Source: UniProtKB cell migration Inferred from mutant phenotype Ref.5. Source: UniProtKB endocardial cushion development Inferred from mutant phenotype Ref.5. Source: UniProtKB fasciculation of motor neuron axon Inferred from mutant phenotype Ref.6. Source: UniProtKB fasciculation of sensory neuron axon Inferred from mutant phenotype PubMed 21791286. Source: UniProtKB regulation of Rho GTPase activity Inferred from sequence or structural similarity. Source: UniProtKB regulation of actin cytoskeleton organization Inferred from sequence or structural similarity. Source: UniProtKB regulation of epithelial to mesenchymal transition Inferred from mutant phenotype Ref.5. Source: UniProtKB regulation of focal adhesion assembly Inferred from sequence or structural similarity. Source: UniProtKB regulation of microtubule cytoskeleton organization Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	early endosome Inferred from sequence or structural similarity. Source: UniProtKB extracellular region Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW GPI-linked ephrin receptor activity Inferred from sequence or structural similarity. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform Long (identifier: P29319-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform Short (identifier: P29319-3)

The sequence of this isoform differs from the canonical sequence as follows:
     531-537: SFSISGE → CMYYFSF
     538-983: Missing.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Signal peptide	1 – 20	20	By similarity
	Chain	21 – 983	963	Ephrin type-A receptor 3		PRO_0000016803
Regions
	Topological domain	21 – 540	520	Extracellular Potential
	Transmembrane	541 – 564	24	Helical; Potential
	Topological domain	565 – 983	419	Cytoplasmic Potential
	Domain	29 – 206	178	Eph LBD
	Domain	324 – 428	105	Fibronectin type-III 1
	Domain	436 – 527	92	Fibronectin type-III 2
	Domain	621 – 882	262	Protein kinase
	Domain	911 – 975	65	SAM
	Nucleotide binding	628 – 633	6	ATP By similarity
	Nucleotide binding	700 – 706	7	ATP By similarity
	Nucleotide binding	750 – 751	2	ATP By similarity
	Motif	981 – 983	3	PDZ-binding Potential
	Compositional bias	188 – 321	134	Cys-rich
Sites
	Active site	746	1	Proton acceptor By similarity
	Binding site	653	1	ATP By similarity
Amino acid modifications
	Modified residue	596	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	602	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	701	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	779	1	Phosphotyrosine; by autocatalysis By similarity
	Modified residue	937	1	Phosphotyrosine Ref.4
	Glycosylation	231	1	N-linked (GlcNAc...) Potential
	Glycosylation	336	1	N-linked (GlcNAc...) Potential
	Glycosylation	390	1	N-linked (GlcNAc...) Potential
	Glycosylation	403	1	N-linked (GlcNAc...) Potential
	Glycosylation	492	1	N-linked (GlcNAc...) Potential
Natural variations
	Alternative sequence	531 – 537	7	SFSISGE → CMYYFSF in isoform Short.		VSP_041882
	Alternative sequence	538 – 983	446	Missing in isoform Short.		VSP_041883

Sequences

	Sequence		Length	Mass (Da)
	Isoform Long [UniParc]. Last modified December 1, 1992. Version 1. Checksum: BE44A6655D8107A2	FASTA	983	109,955
	10 20 30 40 50 60 MDCHLSILVL LGCCVLSCSG ELSPQPSNEV NLLDSKTIQG ELGWISYPSH GWEEISGVDE 70 80 90 100 110 120 HYTPIRTYQV CNVMDHSQNN WLRTNWVPRN SAQKIYVELK FTLRDCNSIP LVLGTCKETF 130 140 150 160 170 180 NLYYMESDDH GVKFREHQFT KIDTIAADES FTQMDLGDRI LKLNTEIREV GPVNKKGFYL 190 200 210 220 230 240 AFQDVGACVA LVSVRVYFKK CPFTVKNLAM FPDTVPMDSQ SLVEVRGSCV NNSKEEDPPR 250 260 270 280 290 300 MYCSTEGEWL VPIGKCTCNA GYEERGFICQ ACRPGFYKAS DGAAKCAKCP PHSSTQEDGS 310 320 330 340 350 360 MNCRCENNYF RAEKDPPSMA CARPPSAPRN VISNINETSV ILDWSWPLDT GGRKDITFNI 370 380 390 400 410 420 ICKKCGWNVR QCEPCSPNVR FLPRQLGLTN TTVTVTDLLA HTNYTFEIDA VNGVSELSSP 430 440 450 460 470 480 PRQYAAVSIT TNQAAPSPVM TIKKDRTSRN SISLSWQEPE HPNGIILDYE VKYYQKQEQE 490 500 510 520 530 540 TSYTILRARG TNVTISSLKP DTTYVFQIRA RTAAGYGTNS RKFEFETSPD SFSISGENSH 550 560 570 580 590 600 VVMIAISAAV AIIVLTVVTY VLVGRFCGYH KSKHSAEEKR LHFGNGHLKL PGLRTYVDPH 610 620 630 640 650 660 TYEDPTQAVH EFAKELDATN ISIDKVVGAG EFGEVCSGRL KLPSKKEISV AIKTLKVGYT 670 680 690 700 710 720 EKQRRDFLGE ASIMGQFDHP NIIRLEGVVT KSKPEMIVTE YMENGSLDSF LRKHDAQFTV 730 740 750 760 770 780 IQLVGMLRGI ASGMKYLSDM GYVHRDLAAR NILINSNLVC KVSDFGLSRV LEDDPEAAYT 790 800 810 820 830 840 TRGGKIPIRW TSPEAMSYRK FTSASDVWSY GIVLWEVMSY GERPYSQMSN QDVIKAVDER 850 860 870 880 890 900 YRLPPPMDCP AALYQLMLDC WQKDRNNRPK FEQIVSILDK LIRNPGSLKI ITSAAARPSN 910 920 930 940 950 960 LLLDQSNVDI ATFHTTGDWL NGMRTAHCKE IFTGVEYSSC DTIAKISTDD MKKVGVTVVG 970 980 PQKKIISTIK ALETQSKNGP VPV
	Isoform Short [UniParc]. Checksum: D698CD2FF29426A5	FASTA	537	60,513
	10 20 30 40 50 60 MDCHLSILVL LGCCVLSCSG ELSPQPSNEV NLLDSKTIQG ELGWISYPSH GWEEISGVDE 70 80 90 100 110 120 HYTPIRTYQV CNVMDHSQNN WLRTNWVPRN SAQKIYVELK FTLRDCNSIP LVLGTCKETF 130 140 150 160 170 180 NLYYMESDDH GVKFREHQFT KIDTIAADES FTQMDLGDRI LKLNTEIREV GPVNKKGFYL 190 200 210 220 230 240 AFQDVGACVA LVSVRVYFKK CPFTVKNLAM FPDTVPMDSQ SLVEVRGSCV NNSKEEDPPR 250 260 270 280 290 300 MYCSTEGEWL VPIGKCTCNA GYEERGFICQ ACRPGFYKAS DGAAKCAKCP PHSSTQEDGS 310 320 330 340 350 360 MNCRCENNYF RAEKDPPSMA CARPPSAPRN VISNINETSV ILDWSWPLDT GGRKDITFNI 370 380 390 400 410 420 ICKKCGWNVR QCEPCSPNVR FLPRQLGLTN TTVTVTDLLA HTNYTFEIDA VNGVSELSSP 430 440 450 460 470 480 PRQYAAVSIT TNQAAPSPVM TIKKDRTSRN SISLSWQEPE HPNGIILDYE VKYYQKQEQE 490 500 510 520 530 TSYTILRARG TNVTISSLKP DTTYVFQIRA RTAAGYGTNS RKFEFETSPD CMYYFSF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification of a new eph-related receptor tyrosine kinase gene from mouse and chicken that is developmentally regulated and encodes at least two forms of the receptor." Sajjadi F.G., Pasquale E.B., Subramani S. New Biol. 3:769-778(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS LONG AND SHORT). Strain: ICR X Swiss Webster. Tissue: Embryo.
[2]	"Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3-expressing 293T and melanoma cells by CrkII and Rho-mediated signalling." Lawrenson I.D., Wimmer-Kleikamp S.H., Lock P., Schoenwaelder S.M., Down M., Boyd A.W., Alewood P.F., Lackmann M. J. Cell Sci. 115:1059-1072(2002) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH CRK.
[3]	"EphA3 null mutants do not demonstrate motor axon guidance defects." Vaidya A., Pniak A., Lemke G., Brown A. Mol. Cell. Biol. 23:8092-8098(2003) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, DEVELOPMENTAL STAGE.
[4]	"Quantitative time-resolved phosphoproteomic analysis of mast cell signaling." Cao L., Yu K., Banh C., Nguyen V., Ritz A., Raphael B.J., Kawakami Y., Kawakami T., Salomon A.R. J. Immunol. 179:5864-5876(2007) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-937, MASS SPECTROMETRY. Tissue: Mast cell.
[5]	"A critical role for the EphA3 receptor tyrosine kinase in heart development." Stephen L.J., Fawkes A.L., Verhoeve A., Lemke G., Brown A. Dev. Biol. 302:66-79(2007) [PubMed] [Europe PMC] [Abstract] Cited for: DISRUPTION PHENOTYPE, FUNCTION IN HEART DEVELOPMENT, DEVELOPMENTAL STAGE.
[6]	"Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling." Gallarda B.W., Bonanomi D., Mueller D., Brown A., Alaynick W.A., Andrews S.E., Lemke G., Pfaff S.L., Marquardt T. Science 320:233-236(2008) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN MOTOR AND SENSORY AXONS SEGREGATION.
[7]	"Regulation of process retraction and cell migration by EphA3 is mediated by the adaptor protein Nck1." Hu T., Shi G., Larose L., Rivera G.M., Mayer B.J., Zhou R. Biochemistry 48:6369-6378(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN CELL MIGRATION, INTERACTION WITH NCK1.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	M68513 mRNA. Translation: AAA39521.1. M68515 mRNA. Translation: AAA39522.1.
IPI	IPI00124182. IPI00223194.
PIR	A45583.
UniGene	Mm.1977.
3D structure databases
ProteinModelPortal	P29319.
SMR	P29319. Positions 29-536, 569-906, 909-975.
ModBase	Search...
PTM databases
PhosphoSite	P29319.
Proteomic databases
PaxDb	P29319.
PRIDE	P29319.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Organism-specific databases
MGI	MGI:99612. Epha3.
Phylogenomic databases
eggNOG	COG0515.
HOVERGEN	HBG062180.
InParanoid	P29319.
OrthoDB	EOG4SXNBR.
Gene expression databases
CleanEx	MM_EPHA3.
Genevestigator	P29319.
GermOnline	ENSMUSG00000052504. 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. 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. IPR011510. SAM_2. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. IPR011641. Tyr-kin_ephrin_A/B_rcpt-like. 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. PF07699. GCC2_GCC3. 1 hit. PF07714. Pkinase_Tyr. 1 hit. PF07647. SAM_2. 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	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
SOURCE	Search...

Entry information

Entry name

EPHA3_MOUSE

Accession

Primary (citable) accession number: P29319

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 1, 1992
Last sequence update:	December 1, 1992
Last modified:	May 1, 2013
This is version 129 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program