P54753 (EPHB3_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

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

Alternative name(s):
EPH-like tyrosine kinase 2
Short name=EPH-like kinase 2
Embryonic kinase 2
Short name=EK2
Short name=hEK2
Tyrosine-protein kinase TYRO6

Gene names

Name:	EPHB3
Synonyms:	ETK2, HEK2, TYRO6

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	998 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 transmembrane ephrin-B 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. Generally has an overlapping and redundant function with EPHB2. Like EPHB2, functions in axon guidance during development regulating for instance the neurons forming the corpus callosum and the anterior commissure, 2 major interhemispheric connections between the temporal lobes of the cerebral cortex. Beside its role in axon guidance plays also an important redundant role with other ephrin-B receptors in development and maturation of dendritic spines and the formation of excitatory synapses. Controls other aspects of development through regulation of cell migration and positioning. This includes angiogenesis, palate development and thymic epithelium development for instance. Forward and reverse signaling through the EFNB2/EPHB3 complex also regulate migration and adhesion of cells that tubularize the urethra and septate the cloaca. Finally, plays an important role in intestinal epithelium differentiation segregating progenitor from differentiated cells in the crypt. Ref.5
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.
Subcellular location	Cell membrane; Single-pass type I membrane protein. Cell projection › dendrite By similarity Ref.5.
Tissue specificity	Ubiquitous.
Post-translational modification	Phosphorylated. Autophosphorylates upon ligand-binding. Autophosphorylation on Tyr-614 is required for interaction with SH2 domain-containing proteins. Ref.1 Ref.4 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
Biological process	Angiogenesis Neurogenesis
Cellular component	Cell membrane Cell projection Membrane
Coding sequence diversity	Polymorphism
Domain	Repeat Signal Transmembrane Transmembrane helix
Ligand	ATP-binding Nucleotide-binding
Molecular function	Developmental protein Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Disulfide bond Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from sequence or structural similarity. Source: UniProtKB axon guidance Inferred from sequence or structural similarity. Source: UniProtKB axonal fasciculation Inferred from sequence or structural similarity. Source: UniProtKB cell migration Inferred from direct assay Ref.5. Source: UniProtKB central nervous system projection neuron axonogenesis Inferred from electronic annotation. Source: Compara corpus callosum development Inferred from sequence or structural similarity. Source: UniProtKB dendritic spine morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB digestive tract morphogenesis Inferred from sequence or structural similarity. Source: UniProtKB palate development Inferred from sequence or structural similarity. Source: UniProtKB positive regulation of synapse assembly Inferred from sequence or structural similarity. Source: UniProtKB protein autophosphorylation Inferred from direct assay Ref.5Ref.1. Source: UniProtKB regulation of Cdc42 GTPase activity Inferred from direct assay Ref.5. Source: UniProtKB regulation of Rac GTPase activity Inferred from direct assay Ref.5. Source: UniProtKB regulation of axonogenesis Inferred from sequence or structural similarity. Source: UniProtKB regulation of cell-cell adhesion Inferred from direct assay Ref.1. Source: UniProtKB retinal ganglion cell axon guidance Inferred from electronic annotation. Source: Compara substrate adhesion-dependent cell spreading Inferred from direct assay Ref.5. Source: UniProtKB thymus development Inferred from sequence or structural similarity. Source: UniProtKB urogenital system development Inferred from sequence or structural similarity. Source: UniProtKB
Cellular_component	dendrite Inferred from electronic annotation. Source: UniProtKB-SubCell integral to plasma membrane Inferred from direct assay Ref.5Ref.1. Source: UniProtKB
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW axon guidance receptor activity Inferred from electronic annotation. Source: Compara ephrin receptor activity Inferred from direct assay Ref.5Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 33

33

Potential

Chain

34 – 998

965

Ephrin type-B receptor 3

PRO_0000016831

Regions

Topological domain

34 – 559

526

Extracellular Potential

Transmembrane

560 – 580

21

Helical; Potential

Topological domain

581 – 998

418

Cytoplasmic Potential

Domain

39 – 217

179

Eph LBD

Domain

340 – 443

104

Fibronectin type-III 1

Domain

453 – 544

92

Fibronectin type-III 2

Domain

633 – 896

264

Protein kinase

Domain

925 – 989

65

SAM

Nucleotide binding

639 – 647

9

ATP By similarity

Motif

996 – 998

3

PDZ-binding Potential

Compositional bias

199 – 336

138

Cys-rich

Sites

Active site

758

1

Proton acceptor By similarity

Binding site

665

1

ATP By similarity

Amino acid modifications

Modified residue

614

1

Phosphotyrosine; by autocatalysis

Glycosylation

351

1

N-linked (GlcNAc...) Potential

Glycosylation

445

1

N-linked (GlcNAc...) Potential

Disulfide bond

81 ↔ 199

Ref.7

Natural variations

Natural variant

168

1

R → L in a lung small cell carcinoma sample; somatic mutation. Ref.8

VAR_042176

Natural variant

440

1

R → C. Ref.8
Corresponds to variant rs56029711 [ dbSNP | Ensembl ].

VAR_042177

Natural variant

579

1

I → V. Ref.8
Corresponds to variant rs56103851 [ dbSNP | Ensembl ].

VAR_042178

Natural variant

601

1

I → L. Ref.8
Corresponds to variant rs56129875 [ dbSNP | Ensembl ].

VAR_042179

Natural variant

724

1

R → W in a lung neuroendocrine carcinoma sample; somatic mutation. Ref.8

VAR_042180

Experimental info

Mutagenesis

614

1

Y → F: Partial loss of phosphorylation and loss of interaction with SH2-containing proteins. Ref.4

Mutagenesis

665

1

K → R: Kinase-dead. Loss of autophosphorylation. Ref.4

Sequence conflict

367

1

G → V in CAA53021. Ref.1

Sequence conflict

406 – 408

3

TER → SEP in CAA53021. Ref.1

Sequence conflict

412

1

I → T in CAA53021. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

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.

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998

Helix Strand Turn

Details...

Beta strand

39 – 44

6

Helix

45 – 47

3

Beta strand

55 – 58

4

Beta strand

63 – 68

6

Beta strand

74 – 80

7

Beta strand

85 – 87

3

Beta strand

90 – 93

4

Beta strand

103 – 114

12

Helix

116 – 118

3

Beta strand

130 – 139

10

Beta strand

155 – 160

6

Beta strand

175 – 181

7

Beta strand

186 – 198

13

Beta strand

200 – 210

11

Sequences

	Sequence		Length	Mass (Da)
	P54753 [UniParc]. Last modified September 27, 2005. Version 2. Checksum: 9B65A4EF58B27407	FASTA	998	110,330
	10 20 30 40 50 60 MARARPPPPP SPPPGLLPLL PPLLLLPLLL LPAGCRALEE TLMDTKWVTS ELAWTSHPES 70 80 90 100 110 120 GWEEVSGYDE AMNPIRTYQV CNVRESSQNN WLRTGFIWRR DVQRVYVELK FTVRDCNSIP 130 140 150 160 170 180 NIPGSCKETF NLFYYEADSD VASASSPFWM ENPYVKVDTI APDESFSRLD AGRVNTKVRS 190 200 210 220 230 240 FGPLSKAGFY LAFQDQGACM SLISVRAFYK KCASTTAGFA LFPETLTGAE PTSLVIAPGT 250 260 270 280 290 300 CIPNAVEVSV PLKLYCNGDG EWMVPVGACT CATGHEPAAK ESQCRPCPPG SYKAKQGEGP 310 320 330 340 350 360 CLPCPPNSRT TSPAASICTC HNNFYRADSD SADSACTTVP SPPRGVISNV NETSLILEWS 370 380 390 400 410 420 EPRDLGGRDD LLYNVICKKC HGAGGASACS RCDDNVEFVP RQLGLTERRV HISHLLAHTR 430 440 450 460 470 480 YTFEVQAVNG VSGKSPLPPR YAAVNITTNQ AAPSEVPTLR LHSSSGSSLT LSWAPPERPN 490 500 510 520 530 540 GVILDYEMKY FEKSEGIAST VTSQMNSVQL DGLRPDARYV VQVRARTVAG YGQYSRPAEF 550 560 570 580 590 600 ETTSERGSGA QQLQEQLPLI VGSATAGLVF VVAVVVIAIV CLRKQRHGSD SEYTEKLQQY 610 620 630 640 650 660 IAPGMKVYID PFTYEDPNEA VREFAKEIDV SCVKIEEVIG AGEFGEVCRG RLKQPGRREV 670 680 690 700 710 720 FVAIKTLKVG YTERQRRDFL SEASIMGQFD HPNIIRLEGV VTKSRPVMIL TEFMENCALD 730 740 750 760 770 780 SFLRLNDGQF TVIQLVGMLR GIAAGMKYLS EMNYVHRDLA ARNILVNSNL VCKVSDFGLS 790 800 810 820 830 840 RFLEDDPSDP TYTSSLGGKI PIRWTAPEAI AYRKFTSASD VWSYGIVMWE VMSYGERPYW 850 860 870 880 890 900 DMSNQDVINA VEQDYRLPPP MDCPTALHQL MLDCWVRDRN LRPKFSQIVN TLDKLIRNAA 910 920 930 940 950 960 SLKVIASAQS GMSQPLLDRT VPDYTTFTTV GDWLDAIKMG RYKESFVSAG FASFDLVAQM 970 980 990 TAEDLLRIGV TLAGHQKKIL SSIQDMRLQM NQTLPVQV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"PCR mediated detection of a new human receptor-tyrosine-kinase, HEK 2." Boehme B., Holtrich U., Wolf G., Luzius H., Grzeschik K.-H., Strebhardt K., Ruebsamen-Waigmann H. Oncogene 8:2857-2862(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], IDENTIFICATION OF EFNB1 AND EFNB2 AS LIGANDS, AUTOPHOSPHORYLATION. Tissue: Embryo.
[2]	"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: Uterus.
[3]	"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.
[4]	"Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions." Hock B., Boehme B., Karn T., Feller S., Ruebsamen-Waigmann H., Strebhardt K. Oncogene 17:255-260(1998) [PubMed] [Europe PMC] [Abstract] Cited for: AUTOPHOSPHORYLATION, MUTAGENESIS OF TYR-614 AND LYS-665.
[5]	"Inhibition of integrin-mediated cell adhesion but not directional cell migration requires catalytic activity of EphB3 receptor tyrosine kinase. Role of Rho family small GTPases." Miao H., Strebhardt K., Pasquale E.B., Shen T.L., Guan J.L., Wang B. J. Biol. Chem. 280:923-932(2005) [PubMed] [Europe PMC] [Abstract] Cited for: AUTOPHOSPHORYLATION, FUNCTION IN CELL ADHESION, FUNCTION IN CELL MIGRATION, SUBCELLULAR LOCATION.
[6]	"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.
[7]	"Ligand binding domain of human EPHB3." Structural genomics consortium (SGC) Submitted (JAN-2011) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 39-211, DISULFIDE BOND.
[8]	"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] LEU-168; CYS-440; VAL-579; LEU-601 AND TRP-724.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X75208 mRNA. Translation: CAA53021.1.
BC052968 mRNA. Translation: AAH52968.1.

IPI

IPI00289329.

PIR

S37627.

RefSeq

NP_004434.2. NM_004443.3.

UniGene

Hs.2913.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
3P1I	X-ray	2.10	A/B/C	39-211	[»]

ProteinModelPortal

P54753.

ModBase

Search...

Protein-protein interaction databases

IntAct

P54753. 2 interactions.

STRING

9606.ENSP00000332118.

PTM databases

PhosphoSite

P54753.

Polymorphism databases

DMDM

76803655.

Proteomic databases

PaxDb

P54753.

PRIDE

P54753.

Protocols and materials databases

DNASU

2049.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000330394; ENSP00000332118; ENSG00000182580.

GeneID

2049.

KEGG

hsa:2049.

UCSC

uc003foz.3. human.

Organism-specific databases

CTD

2049.

GeneCards

GC03P184279.

HGNC

HGNC:3394. EPHB3.

HPA

HPA007698.
HPA008184.

MIM

601839. gene.

neXtProt

NX_P54753.

PharmGKB

PA27826.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0515.

HOGENOM

HOG000233856.

HOVERGEN

HBG062180.

InParanoid

P54753.

KO

K05112.

OMA

LQQYITP.

OrthoDB

EOG4W9J35.

PhylomeDB

P54753.

Enzyme and pathway databases

BRENDA

2.7.10.1. 2681.

Pathway_Interaction_DB

ephbfwdpathway. EPHB forward signaling.
ephrinb_ephbpathway. EphrinB-EPHB pathway.

Gene expression databases

ArrayExpress

P54753.

Bgee

P54753.

CleanEx

HS_EPHB3.

Genevestigator

P54753.

GermOnline

ENSG00000182580. 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.
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.
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.
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

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

P54753.

ChEMBL

CHEMBL4901.

EvolutionaryTrace

P54753.

GenomeRNAi

2049.

NextBio

8331.

SOURCE

Search...

Entry information

Entry name

EPHB3_HUMAN

Accession

Primary (citable) accession number: P54753
Secondary accession number(s): Q7Z740

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	September 27, 2005
Last modified:	May 1, 2013
This is version 136 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.