Reviewed, UniProtKB/Swiss-Prot P54760 (EPHB4_HUMAN)

Names and origin

Protein names

Recommended name:
    Ephrin type-B receptor 4
    EC=2.7.10.1
Alternative name(s):
    Tyrosine-protein kinase receptor HTK
    Tyrosine-protein kinase TYRO11

Gene names

Name:	EPHB4
Synonyms:	HTK, TYRO11

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	987 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 for members of the ephrin-B family. Binds to ephrin-B2. May have a role in events mediating differentiation and development.
Catalytic activity	ATP + a [protein]-L-tyrosine = ADP + a [protein]-L-tyrosine phosphate.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	Abundantly expressed in placenta and in a range of primary tissues and malignant cell lines. Expressed in fetal, but not adult, brain, and in primitive and myeloid, but not lymphoid, hematopoietic cells.
Post-translational modification	Autophosphorylated. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8
Sequence similarities	Belongs to the protein kinase superfamily. Tyr protein kinase family. Ephrin receptor subfamily. Contains 2 fibronectin type-III domains. Contains 1 protein kinase domain. Contains 1 SAM (sterile alpha motif) domain.

Ontologies

Keywords
Cellular component	Membrane
Coding sequence diversity	Polymorphism
Domain	Repeat Signal Transmembrane
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Receptor Transferase Tyrosine-protein kinase
PTM	Glycoprotein Phosphoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	cell proliferation Traceable author statement. Source: ProtInc organ morphogenesis Traceable author statement. Source: ProtInc protein amino acid phosphorylation Inferred from electronic annotation. Source: InterPro regulation of angiogenesis Non-traceable author statement. Source: UniProtKB transmembrane receptor protein tyrosine kinase signaling pathway Inferred from electronic annotation. Source: InterPro
Cellular component	cell surface Inferred from direct assay. Source: UniProtKB integral to plasma membrane Ref.1 Traceable author statement. Source: ProtInc
Molecular function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW ephrin receptor activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 15

15

Potential

Chain

16 – 987

972

Ephrin type-B receptor 4

PRO_0000016834

Regions

Topological domain

16 – 539

524

Extracellular Potential

Transmembrane

540 – 560

21

Potential

Topological domain

561 – 987

427

Cytoplasmic Potential

Domain

323 – 428

106

Fibronectin type-III 1

Domain

434 – 526

93

Fibronectin type-III 2

Domain

615 – 899

285

Protein kinase

Domain

907 – 971

65

SAM

Nucleotide binding

621 – 629

9

ATP By similarity

Motif

985 – 987

3

PDZ-binding Potential

Compositional bias

184 – 320

137

Cys-rich

Sites

Active site

740

1

Proton acceptor By similarity

Binding site

647

1

ATP By similarity

Amino acid modifications

Modified residue

574

1

Phosphotyrosine Ref.8

Modified residue

614

1

Phosphotyrosine

Modified residue

769

1

Phosphoserine Ref.5

Modified residue

770

1

Phosphoserine

Modified residue

774

1

Phosphotyrosine Ref.5 Ref.8

Modified residue

775

1

Phosphothreonine

Modified residue

776

1

Phosphoserine

Modified residue

906

1

Phosphotyrosine

Modified residue

907

1

Phosphoserine

Modified residue

911

1

Phosphoserine Ref.5

Modified residue

953

1

Phosphothreonine Ref.5

Modified residue

976

1

Phosphothreonine Ref.5 Ref.6 Ref.7

Modified residue

987

1

Phosphotyrosine Ref.8

Glycosylation

203

1

N-linked (GlcNAc...) Potential

Glycosylation

335

1

N-linked (GlcNAc...) Potential

Glycosylation

426

1

N-linked (GlcNAc...) Potential

Natural variations

Natural variant

67

1

P → L: dbSNP rs34653459. Ref.11

VAR_042181

Natural variant

113

1

V → I: dbSNP rs55866373. Ref.11

VAR_042182

Natural variant

346

1

P → L in a metastatic melanoma sample; somatic mutation. Ref.11

VAR_042183

Natural variant

371

1

A → V: dbSNP rs55720981. Ref.11

VAR_042184

Natural variant

576

1

D → E: dbSNP rs36050247. Ref.11

VAR_042185

Natural variant

678

1

R → H: dbSNP rs55692440. Ref.11

VAR_042186

Natural variant

882

1

A → T: dbSNP rs34918225. Ref.11

VAR_042187

Natural variant

889

1

R → W in a gastric adenocarcinoma sample; somatic mutation. Ref.11

VAR_042188

Natural variant

890

1

E → D: dbSNP rs35638378. Ref.11

VAR_042189

Experimental info

Sequence conflict

62

1

D → E in AAA20598. Ref.1

Sequence conflict

308

1

Y → D in AAA20598. Ref.1

Sequence conflict

464

1

V → W in AAA20598. Ref.1

Sequence conflict

926 – 927

2

ES → AR in AAA20598. Ref.1

Secondary structure

1

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987

Helix Strand Turn

Details...

Beta strand

17 – 22

6

Helix

23 – 25

3

Beta strand

33 – 36

4

Beta strand

43 – 48

6

Beta strand

54 – 61

8

Beta strand

63 – 65

3

Beta strand

70 – 74

5

Beta strand

84 – 95

12

Helix

97 – 99

3

Beta strand

109 – 121

13

Beta strand

130 – 132

3

Beta strand

135 – 142

8

Beta strand

160 – 166

7

Beta strand

171 – 182

12

Beta strand

184 – 196

13

Beta strand

441 – 446

6

Beta strand

449 – 453

5

Beta strand

460 – 462

3

Beta strand

466 – 473

8

Turn

479 – 481

3

Beta strand

482 – 496

15

Beta strand

503 – 510

8

Helix

612 – 614

3

Beta strand

615 – 623

9

Beta strand

625 – 634

10

Beta strand

642 – 649

8

Helix

656 – 668

13

Beta strand

679 – 683

5

Beta strand

685 – 694

10

Helix

701 – 707

7

Turn

708 – 710

3

Helix

714 – 733

20

Helix

743 – 745

3

Beta strand

746 – 748

3

Beta strand

754 – 756

3

Helix

784 – 786

3

Helix

789 – 794

6

Helix

799 – 814

16

Turn

820 – 823

4

Helix

826 – 834

9

Helix

847 – 856

10

Helix

861 – 863

3

Helix

867 – 879

13

Helix

881 – 885

5

Helix

912 – 918

7

Helix

922 – 924

3

Helix

925 – 930

6

Helix

936 – 939

4

Helix

944 – 950

7

Helix

955 – 965

11

Sequences

	Sequence		Length	Mass (Da)
	P54760-1 [UniParc]. Last modified October 18, 2001. Version 2. Checksum: 11A004622F194706	FASTA	987	108,270
	10 20 30 40 50 60 MELRVLLCWA SLAAALEETL LNTKLETADL KWVTFPQVDG QWEELSGLDE EQHSVRTYEV 70 80 90 100 110 120 CDVQRAPGQA HWLRTGWVPR RGAVHVYATL RFTMLECLSL PRAGRSCKET FTVFYYESDA 130 140 150 160 170 180 DTATALTPAW MENPYIKVDT VAAEHLTRKR PGAEATGKVN VKTLRLGPLS KAGFYLAFQD 190 200 210 220 230 240 QGACMALLSL HLFYKKCAQL TVNLTRFPET VPRELVVPVA GSCVVDAVPA PGPSPSLYCR 250 260 270 280 290 300 EDGQWAEQPV TGCSCAPGFE AAEGNTKCRA CAQGTFKPLS GEGSCQPCPA NSHSNTIGSA 310 320 330 340 350 360 VCQCRVGYFR ARTDPRGAPC TTPPSAPRSV VSRLNGSSLH LEWSAPLESG GREDLTYALR 370 380 390 400 410 420 CRECRPGGSC APCGGDLTFD PGPRDLVEPW VVVRGLRPDF TYTFEVTALN GVSSLATGPV 430 440 450 460 470 480 PFEPVNVTTD REVPPAVSDI RVTRSSPSSL SLAWAVPRAP SGAVLDYEVK YHEKGAEGPS 490 500 510 520 530 540 SVRFLKTSEN RAELRGLKRG ASYLVQVRAR SEAGYGPFGQ EHHSQTQLDE SEGWREQLAL 550 560 570 580 590 600 IAGTAVVGVV LVLVVIVVAV LCLRKQSNGR EAEYSDKHGQ YLIGHGTKVY IDPFTYEDPN 610 620 630 640 650 660 EAVREFAKEI DVSYVKIEEV IGAGEFGEVC RGRLKAPGKK ESCVAIKTLK GGYTERQRRE 670 680 690 700 710 720 FLSEASIMGQ FEHPNIIRLE GVVTNSMPVM ILTEFMENGA LDSFLRLNDG QFTVIQLVGM 730 740 750 760 770 780 LRGIASGMRY LAEMSYVHRD LAARNILVNS NLVCKVSDFG LSRFLEENSS DPTYTSSLGG 790 800 810 820 830 840 KIPIRWTAPE AIAFRKFTSA SDAWSYGIVM WEVMSFGERP YWDMSNQDVI NAIEQDYRLP 850 860 870 880 890 900 PPPDCPTSLH QLMLDCWQKD RNARPRFPQV VSALDKMIRN PASLKIVARE NGGASHPLLD 910 920 930 940 950 960 QRQPHYSAFG SVGEWLRAIK MGRYEESFAA AGFGSFELVS QISAEDLLRI GVTLAGHQKK 970 980 ILASVQHMKS QAKPGTPGGT GGPAPQY

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of HTK, a novel transmembrane tyrosine kinase of the EPH subfamily." Bennett B.D., Wang Z., Kuang W.J., Wang A., Groopman J.E., Goeddel D.V., Scadden D.T. J. Biol. Chem. 269:14211-14218(1994) [PubMed: 8188704] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Comparative analysis of the gene-dense ACHE/TFR2 region on human chromosome 7q22 with the orthologous region on mouse chromosome 5." Wilson M.D., Riemer C., Martindale D.W., Schnupf P., Boright A.P., Cheung T.L., Hardy D.M., Schwartz S., Scherer S.W., Tsui L.-C., Miller W., Koop B.F. Nucleic Acids Res. 29:1352-1365(2001) [PubMed: 11239002] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[3]	"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: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 143-987. Tissue: Pancreas.
[4]	"Time-resolved mass spectrometry of tyrosine phosphorylation sites in the epidermal growth factor receptor signaling network reveals dynamic modules." Zhang Y., Wolf-Yadlin A., Ross P.L., Pappin D.J., Rush J., Lauffenburger D.A., White F.M. Mol. Cell. Proteomics 4:1240-1250(2005) [PubMed: 15951569] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-590 AND TYR-596, MASS SPECTROMETRY. Tissue: Epithelium.
[5]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed: 18691976] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-769; TYR-774; SER-911; THR-953 AND THR-976, MASS SPECTROMETRY.
[6]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed: 18669648] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-976, MASS SPECTROMETRY.
[7]	"Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach." Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S. Anal. Chem. 81:4493-4501(2009) [PubMed: 19413330] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-976, MASS SPECTROMETRY.
[8]	"An extensive survey of tyrosine phosphorylation revealing new sites in human mammary epithelial cells." Heibeck T.H., Ding S.-J., Opresko L.K., Zhao R., Schepmoes A.A., Yang F., Tolmachev A.V., Monroe M.E., Camp D.G. II, Smith R.D., Wiley H.S., Qian W.-J. J. Proteome Res. 8:3852-3861(2009) [PubMed: 19534553] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-574; TYR-774 AND TYR-987, MASS SPECTROMETRY. Tissue: Mammary epithelium.
[9]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-574; TYR-614; SER-769; SER-770; TYR-774; THR-775; SER-776; TYR-906; SER-907; SER-911; THR-976 AND TYR-987, MASS SPECTROMETRY.
[10]	"Solution structure of the second FN3 domain from human ephrin type-B receptor 4." RIKEN structural genomics initiative (RSGI) Submitted (JUL-2007) to the PDB data bank Cited for: STRUCTURE BY NMR OF 434-529.
[11]	"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: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] LEU-67; ILE-113; LEU-346; VAL-371; GLU-576; HIS-678; THR-882; TRP-889 AND ASP-890.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

U07695 mRNA. Translation: AAA20598.1.
AF312032 Genomic DNA. Translation: AAK21010.1.
BC004264 mRNA. Translation: AAH04264.1.

IPI

IPI00289342.

PIR

A54092.

RefSeq

NP_004435.3.

UniGene

Hs.437008

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2BBA	X-ray	1.65	A	17-196	[»]
2E7H	NMR	-	A	434-529	[»]
2HLE	X-ray	2.05	A	17-196	[»]
2QKQ	X-ray	2.10	A/B	896-977	[»]
2VWU	X-ray	2.00	A	598-887	[»]
2VWV	X-ray	1.90	A	598-899	[»]
2VWW	X-ray	1.90	A	598-899	[»]
2VWX	X-ray	1.65	A	598-899	[»]
2VWY	X-ray	1.65	A	598-899	[»]
2VWZ	X-ray	1.65	A	598-899	[»]
2VX0	X-ray	2.10	A	598-899	[»]
2VX1	X-ray	1.65	A	598-899	[»]

SMR

P54760. Positions 318-413, 322-529, 590-901.

ModBase

Search...

Protein-protein interaction databases

STRING

P54760.

PTM databases

PhosphoSite

P54760.

2-D gel databases

DOSAC-COBS-2DPAGE

P54760.

Proteomic databases

PRIDE

P54760.

Genome annotation databases

Ensembl

ENST00000358173; ENSP00000350896; ENSG00000196411; Homo sapiens. [Genome view]

GeneID

2050.

KEGG

hsa:2050.

UCSC

uc003uwn.1. human.

Organism-specific databases

CTD

2050.

GeneCards

GC07M100238.

H-InvDB

HIX0025312.

HGNC

HGNC:3395. EPHB4.

HPA

CAB013537.

MIM

600011. gene.

PharmGKB

PA27827.

GenAtlas

Search...

Phylogenomic databases

eggNOG

prNOG04086.

HOGENOM

HBG755340.

HOVERGEN

P54760.

InParanoid

P54760.

OMA

YIKVDTV.

OrthoDB

EOG9PZMS0.

PhylomeDB

P54760.

Enzyme and pathway databases

BRENDA

2.7.10.1. 247.

Pathway_Interaction_DB

ephbfwdpathway. EPHB forward signaling.
ephrinbrevpathway. Ephrin B reverse signaling.
ephrinb_ephbpathway. EphrinB-EPHB pathway.

Gene expression databases

ArrayExpress

P54760.

Bgee

P54760.

CleanEx

HS_EPHB4.

Genevestigator

P54760.

GermOnline

ENSG00000196411. Homo sapiens.

Family and domain databases

InterPro

IPR001090. Ephrin_rcpt_lig-bd.
IPR008957. Fibronectin_typ-III-like_fold.
IPR003961. FN_III.
IPR008979. Galactose-bd-like.
IPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_cat_dom.
IPR017441. Protein_kinase_ATP_BS.
IPR001660. SAM.
IPR010993. SAM_homology.
IPR013761. SAM_type.
IPR021129. SAM_type1.
IPR020635. Tyr_Pkinase_cat_dom.
IPR020685. Tyr_prot_kinase.
IPR008266. Tyr_prot_kinase_AS.
IPR016257. Tyr_prot_kinase_ephrin_rcpt.
IPR001426. Tyr_prot_kinase_rcpt_V_CS.
[Graphical view]

Gene3D

G3DSA:2.60.40.30. FN_III-like. 2 hits.
G3DSA:1.10.150.50. SAM_type. 1 hit.

PANTHER

PTHR23256. Tyr_prot_kinase. 1 hit.

Pfam

PF01404. Ephrin_lbd. 1 hit.
PF00041. fn3. 2 hits.
PF00536. SAM_1. 1 hit.
[Graphical view]

PIRSF

PIRSF000666. TyrPK_ephrin_receptor. 1 hit.

SMART

SM00615. EPH_lbd. 1 hit.
SM00060. FN3. 2 hits.
SM00454. SAM. 1 hit.
SM00219. TyrKc. 1 hit.
[Graphical view]

PROSITE

PS01186. EGF_2. 1 hit. Uncertain.
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 Resources

NextBio

8335.

SOURCE

Search...

Entry information

Entry name

EPHB4_HUMAN

Accession

Primary (citable) accession number: P54760
Secondary accession number(s): Q9BTA5, Q9BXP0

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 18, 2001
Last modified:	February 9, 2010
This is version 118 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

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.