Full text data of EPHB3
EPHB3
(ETK2, HEK2, TYRO6)
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Ephrin type-B receptor 3; 2.7.10.1 (EPH-like tyrosine kinase 2; EPH-like kinase 2; Embryonic kinase 2; EK2; hEK2; Tyrosine-protein kinase TYRO6; Flags: Precursor)
Ephrin type-B receptor 3; 2.7.10.1 (EPH-like tyrosine kinase 2; EPH-like kinase 2; Embryonic kinase 2; EK2; hEK2; Tyrosine-protein kinase TYRO6; Flags: Precursor)
UniProt
P54753
ID EPHB3_HUMAN Reviewed; 998 AA.
AC P54753; Q7Z740;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 27-SEP-2005, sequence version 2.
DT 22-JAN-2014, entry version 143.
DE RecName: Full=Ephrin type-B receptor 3;
DE EC=2.7.10.1;
DE AltName: Full=EPH-like tyrosine kinase 2;
DE Short=EPH-like kinase 2;
DE AltName: Full=Embryonic kinase 2;
DE Short=EK2;
DE Short=hEK2;
DE AltName: Full=Tyrosine-protein kinase TYRO6;
DE Flags: Precursor;
GN Name=EPHB3; Synonyms=ETK2, HEK2, TYRO6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], IDENTIFICATION OF EFNB1 AND EFNB2 AS
RP LIGANDS, AND AUTOPHOSPHORYLATION.
RC TISSUE=Embryo;
RX PubMed=8397371;
RA Boehme B., Holtrich U., Wolf G., Luzius H., Grzeschik K.-H.,
RA Strebhardt K., Ruebsamen-Waigmann H.;
RT "PCR mediated detection of a new human receptor-tyrosine-kinase, HEK
RT 2.";
RL Oncogene 8:2857-2862(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NOMENCLATURE.
RX PubMed=9267020;
RG Eph nomenclature committee;
RT "Unified nomenclature for Eph family receptors and their ligands, the
RT ephrins.";
RL Cell 90:403-404(1997).
RN [4]
RP AUTOPHOSPHORYLATION, AND MUTAGENESIS OF TYR-614 AND LYS-665.
RX PubMed=9674711; DOI=10.1038/sj.onc.1201907;
RA Hock B., Boehme B., Karn T., Feller S., Ruebsamen-Waigmann H.,
RA Strebhardt K.;
RT "Tyrosine-614, the major autophosphorylation site of the receptor
RT tyrosine kinase HEK2, functions as multi-docking site for SH2-domain
RT mediated interactions.";
RL Oncogene 17:255-260(1998).
RN [5]
RP AUTOPHOSPHORYLATION, FUNCTION IN CELL ADHESION, FUNCTION IN CELL
RP MIGRATION, AND SUBCELLULAR LOCATION.
RX PubMed=15536074; DOI=10.1074/jbc.M411383200;
RA Miao H., Strebhardt K., Pasquale E.B., Shen T.L., Guan J.L., Wang B.;
RT "Inhibition of integrin-mediated cell adhesion but not directional
RT cell migration requires catalytic activity of EphB3 receptor tyrosine
RT kinase. Role of Rho family small GTPases.";
RL J. Biol. Chem. 280:923-932(2005).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 39-211, AND DISULFIDE BOND.
RG Structural genomics consortium (SGC);
RT "Ligand binding domain of human EPHB3.";
RL Submitted (JAN-2011) to the PDB data bank.
RN [8]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-168; CYS-440; VAL-579; LEU-601 AND
RP TRP-724.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Receptor tyrosine kinase which binds promiscuously
CC transmembrane ephrin-B family ligands residing on adjacent cells,
CC leading to contact-dependent bidirectional signaling into
CC neighboring cells. The signaling pathway downstream of the
CC receptor is referred to as forward signaling while the signaling
CC pathway downstream of the ephrin ligand is referred to as reverse
CC signaling. Generally has an overlapping and redundant function
CC with EPHB2. Like EPHB2, functions in axon guidance during
CC development regulating for instance the neurons forming the corpus
CC callosum and the anterior commissure, 2 major interhemispheric
CC connections between the temporal lobes of the cerebral cortex.
CC Beside its role in axon guidance plays also an important redundant
CC role with other ephrin-B receptors in development and maturation
CC of dendritic spines and the formation of excitatory synapses.
CC Controls other aspects of development through regulation of cell
CC migration and positioning. This includes angiogenesis, palate
CC development and thymic epithelium development for instance.
CC Forward and reverse signaling through the EFNB2/EPHB3 complex also
CC regulate migration and adhesion of cells that tubularize the
CC urethra and septate the cloaca. Finally, plays an important role
CC in intestinal epithelium differentiation segregating progenitor
CC from differentiated cells in the crypt.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- SUBUNIT: Heterotetramer upon binding of the ligand. The
CC heterotetramer is composed of an ephrin dimer and a receptor
CC dimer. Oligomerization is probably required to induce biological
CC responses (By similarity).
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Cell projection, dendrite (By similarity).
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Phosphorylated. Autophosphorylates upon ligand-binding.
CC Autophosphorylation on Tyr-614 is required for interaction with
CC SH2 domain-containing proteins.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Ephrin receptor subfamily.
CC -!- SIMILARITY: Contains 1 Eph LBD (Eph ligand-binding) domain.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 SAM (sterile alpha motif) domain.
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DR EMBL; X75208; CAA53021.1; -; mRNA.
DR EMBL; BC052968; AAH52968.1; -; mRNA.
DR PIR; S37627; S37627.
DR RefSeq; NP_004434.2; NM_004443.3.
DR UniGene; Hs.2913; -.
DR PDB; 3P1I; X-ray; 2.10 A; A/B/C=39-211.
DR PDBsum; 3P1I; -.
DR ProteinModelPortal; P54753; -.
DR SMR; P54753; 37-906, 922-992.
DR IntAct; P54753; 3.
DR MINT; MINT-1538099; -.
DR STRING; 9606.ENSP00000332118; -.
DR BindingDB; P54753; -.
DR ChEMBL; CHEMBL4901; -.
DR GuidetoPHARMACOLOGY; 1832; -.
DR PhosphoSite; P54753; -.
DR DMDM; 76803655; -.
DR PaxDb; P54753; -.
DR PRIDE; P54753; -.
DR DNASU; 2049; -.
DR Ensembl; ENST00000330394; ENSP00000332118; ENSG00000182580.
DR GeneID; 2049; -.
DR KEGG; hsa:2049; -.
DR UCSC; uc003foz.3; human.
DR CTD; 2049; -.
DR GeneCards; GC03P184279; -.
DR HGNC; HGNC:3394; EPHB3.
DR HPA; HPA007698; -.
DR HPA; HPA008184; -.
DR MIM; 601839; gene.
DR neXtProt; NX_P54753; -.
DR PharmGKB; PA27826; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233856; -.
DR HOVERGEN; HBG062180; -.
DR InParanoid; P54753; -.
DR KO; K05112; -.
DR OMA; LQQYITP; -.
DR OrthoDB; EOG7VTDM6; -.
DR PhylomeDB; P54753; -.
DR BRENDA; 2.7.10.1; 2681.
DR SignaLink; P54753; -.
DR EvolutionaryTrace; P54753; -.
DR GeneWiki; EPHB3; -.
DR GenomeRNAi; 2049; -.
DR NextBio; 8331; -.
DR PRO; PR:P54753; -.
DR ArrayExpress; P54753; -.
DR Bgee; P54753; -.
DR CleanEx; HS_EPHB3; -.
DR Genevestigator; P54753; -.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008046; F:axon guidance receptor activity; IEA:Ensembl.
DR GO; GO:0005003; F:ephrin receptor activity; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; ISS:UniProtKB.
DR GO; GO:0007411; P:axon guidance; ISS:UniProtKB.
DR GO; GO:0007413; P:axonal fasciculation; ISS:UniProtKB.
DR GO; GO:0016477; P:cell migration; IDA:UniProtKB.
DR GO; GO:0021952; P:central nervous system projection neuron axonogenesis; IEA:Ensembl.
DR GO; GO:0022038; P:corpus callosum development; ISS:UniProtKB.
DR GO; GO:0060997; P:dendritic spine morphogenesis; ISS:UniProtKB.
DR GO; GO:0048546; P:digestive tract morphogenesis; ISS:UniProtKB.
DR GO; GO:0060021; P:palate development; ISS:UniProtKB.
DR GO; GO:0051965; P:positive regulation of synapse assembly; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0050770; P:regulation of axonogenesis; ISS:UniProtKB.
DR GO; GO:0043088; P:regulation of Cdc42 GTPase activity; IDA:UniProtKB.
DR GO; GO:0022407; P:regulation of cell-cell adhesion; IDA:UniProtKB.
DR GO; GO:0032314; P:regulation of Rac GTPase activity; IDA:UniProtKB.
DR GO; GO:0031290; P:retinal ganglion cell axon guidance; IEA:Ensembl.
DR GO; GO:0034446; P:substrate adhesion-dependent cell spreading; IDA:UniProtKB.
DR GO; GO:0048538; P:thymus development; ISS:UniProtKB.
DR GO; GO:0001655; P:urogenital system development; ISS:UniProtKB.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.60.120.260; -; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR027936; Eph_TM.
DR InterPro; IPR001090; Ephrin_rcpt_lig-bd_dom.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR008979; Galactose-bd-like.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR021129; SAM_type1.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR011641; Tyr-kin_ephrin_A/B_rcpt-like.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016257; Tyr_kinase_ephrin_rcpt.
DR InterPro; IPR001426; Tyr_kinase_rcpt_V_CS.
DR Pfam; PF14575; EphA2_TM; 1.
DR Pfam; PF01404; Ephrin_lbd; 1.
DR Pfam; PF00041; fn3; 2.
DR Pfam; PF07699; GCC2_GCC3; 1.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR Pfam; PF00536; SAM_1; 1.
DR PIRSF; PIRSF000666; TyrPK_ephrin_receptor; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00615; EPH_lbd; 1.
DR SMART; SM00060; FN3; 2.
DR SMART; SM00454; SAM; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51550; EPH_LBD; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00790; RECEPTOR_TYR_KIN_V_1; 1.
DR PROSITE; PS00791; RECEPTOR_TYR_KIN_V_2; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Angiogenesis; ATP-binding; Cell membrane;
KW Cell projection; Complete proteome; Developmental protein;
KW Disulfide bond; Glycoprotein; Kinase; Membrane; Neurogenesis;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Receptor;
KW Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase.
FT SIGNAL 1 33 Potential.
FT CHAIN 34 998 Ephrin type-B receptor 3.
FT /FTId=PRO_0000016831.
FT TOPO_DOM 34 559 Extracellular (Potential).
FT TRANSMEM 560 580 Helical; (Potential).
FT TOPO_DOM 581 998 Cytoplasmic (Potential).
FT DOMAIN 39 217 Eph LBD.
FT DOMAIN 339 451 Fibronectin type-III 1.
FT DOMAIN 452 545 Fibronectin type-III 2.
FT DOMAIN 633 896 Protein kinase.
FT DOMAIN 925 989 SAM.
FT NP_BIND 639 647 ATP (By similarity).
FT MOTIF 996 998 PDZ-binding (Potential).
FT COMPBIAS 199 336 Cys-rich.
FT ACT_SITE 758 758 Proton acceptor (By similarity).
FT BINDING 665 665 ATP (By similarity).
FT MOD_RES 614 614 Phosphotyrosine; by autocatalysis.
FT CARBOHYD 351 351 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 445 445 N-linked (GlcNAc...) (Potential).
FT DISULFID 81 199
FT VARIANT 168 168 R -> L (in a lung small cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_042176.
FT VARIANT 440 440 R -> C (in dbSNP:rs56029711).
FT /FTId=VAR_042177.
FT VARIANT 579 579 I -> V (in dbSNP:rs56103851).
FT /FTId=VAR_042178.
FT VARIANT 601 601 I -> L (in dbSNP:rs56129875).
FT /FTId=VAR_042179.
FT VARIANT 724 724 R -> W (in a lung neuroendocrine
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_042180.
FT MUTAGEN 614 614 Y->F: Partial loss of phosphorylation and
FT loss of interaction with SH2-containing
FT proteins.
FT MUTAGEN 665 665 K->R: Kinase-dead. Loss of
FT autophosphorylation.
FT CONFLICT 367 367 G -> V (in Ref. 1; CAA53021).
FT CONFLICT 406 408 TER -> SEP (in Ref. 1; CAA53021).
FT CONFLICT 412 412 I -> T (in Ref. 1; CAA53021).
FT STRAND 39 44
FT HELIX 45 47
FT STRAND 55 58
FT STRAND 63 68
FT STRAND 74 80
FT STRAND 85 87
FT STRAND 90 93
FT STRAND 103 114
FT HELIX 116 118
FT STRAND 130 139
FT STRAND 155 160
FT STRAND 175 181
FT STRAND 186 198
FT STRAND 200 210
SQ SEQUENCE 998 AA; 110330 MW; 9B65A4EF58B27407 CRC64;
MARARPPPPP SPPPGLLPLL PPLLLLPLLL LPAGCRALEE TLMDTKWVTS ELAWTSHPES
GWEEVSGYDE AMNPIRTYQV CNVRESSQNN WLRTGFIWRR DVQRVYVELK FTVRDCNSIP
NIPGSCKETF NLFYYEADSD VASASSPFWM ENPYVKVDTI APDESFSRLD AGRVNTKVRS
FGPLSKAGFY LAFQDQGACM SLISVRAFYK KCASTTAGFA LFPETLTGAE PTSLVIAPGT
CIPNAVEVSV PLKLYCNGDG EWMVPVGACT CATGHEPAAK ESQCRPCPPG SYKAKQGEGP
CLPCPPNSRT TSPAASICTC HNNFYRADSD SADSACTTVP SPPRGVISNV NETSLILEWS
EPRDLGGRDD LLYNVICKKC HGAGGASACS RCDDNVEFVP RQLGLTERRV HISHLLAHTR
YTFEVQAVNG VSGKSPLPPR YAAVNITTNQ AAPSEVPTLR LHSSSGSSLT LSWAPPERPN
GVILDYEMKY FEKSEGIAST VTSQMNSVQL DGLRPDARYV VQVRARTVAG YGQYSRPAEF
ETTSERGSGA QQLQEQLPLI VGSATAGLVF VVAVVVIAIV CLRKQRHGSD SEYTEKLQQY
IAPGMKVYID PFTYEDPNEA VREFAKEIDV SCVKIEEVIG AGEFGEVCRG RLKQPGRREV
FVAIKTLKVG YTERQRRDFL SEASIMGQFD HPNIIRLEGV VTKSRPVMIL TEFMENCALD
SFLRLNDGQF TVIQLVGMLR GIAAGMKYLS EMNYVHRDLA ARNILVNSNL VCKVSDFGLS
RFLEDDPSDP TYTSSLGGKI PIRWTAPEAI AYRKFTSASD VWSYGIVMWE VMSYGERPYW
DMSNQDVINA VEQDYRLPPP MDCPTALHQL MLDCWVRDRN LRPKFSQIVN TLDKLIRNAA
SLKVIASAQS GMSQPLLDRT VPDYTTFTTV GDWLDAIKMG RYKESFVSAG FASFDLVAQM
TAEDLLRIGV TLAGHQKKIL SSIQDMRLQM NQTLPVQV
//
ID EPHB3_HUMAN Reviewed; 998 AA.
AC P54753; Q7Z740;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 27-SEP-2005, sequence version 2.
DT 22-JAN-2014, entry version 143.
DE RecName: Full=Ephrin type-B receptor 3;
DE EC=2.7.10.1;
DE AltName: Full=EPH-like tyrosine kinase 2;
DE Short=EPH-like kinase 2;
DE AltName: Full=Embryonic kinase 2;
DE Short=EK2;
DE Short=hEK2;
DE AltName: Full=Tyrosine-protein kinase TYRO6;
DE Flags: Precursor;
GN Name=EPHB3; Synonyms=ETK2, HEK2, TYRO6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], IDENTIFICATION OF EFNB1 AND EFNB2 AS
RP LIGANDS, AND AUTOPHOSPHORYLATION.
RC TISSUE=Embryo;
RX PubMed=8397371;
RA Boehme B., Holtrich U., Wolf G., Luzius H., Grzeschik K.-H.,
RA Strebhardt K., Ruebsamen-Waigmann H.;
RT "PCR mediated detection of a new human receptor-tyrosine-kinase, HEK
RT 2.";
RL Oncogene 8:2857-2862(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [3]
RP NOMENCLATURE.
RX PubMed=9267020;
RG Eph nomenclature committee;
RT "Unified nomenclature for Eph family receptors and their ligands, the
RT ephrins.";
RL Cell 90:403-404(1997).
RN [4]
RP AUTOPHOSPHORYLATION, AND MUTAGENESIS OF TYR-614 AND LYS-665.
RX PubMed=9674711; DOI=10.1038/sj.onc.1201907;
RA Hock B., Boehme B., Karn T., Feller S., Ruebsamen-Waigmann H.,
RA Strebhardt K.;
RT "Tyrosine-614, the major autophosphorylation site of the receptor
RT tyrosine kinase HEK2, functions as multi-docking site for SH2-domain
RT mediated interactions.";
RL Oncogene 17:255-260(1998).
RN [5]
RP AUTOPHOSPHORYLATION, FUNCTION IN CELL ADHESION, FUNCTION IN CELL
RP MIGRATION, AND SUBCELLULAR LOCATION.
RX PubMed=15536074; DOI=10.1074/jbc.M411383200;
RA Miao H., Strebhardt K., Pasquale E.B., Shen T.L., Guan J.L., Wang B.;
RT "Inhibition of integrin-mediated cell adhesion but not directional
RT cell migration requires catalytic activity of EphB3 receptor tyrosine
RT kinase. Role of Rho family small GTPases.";
RL J. Biol. Chem. 280:923-932(2005).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [7]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 39-211, AND DISULFIDE BOND.
RG Structural genomics consortium (SGC);
RT "Ligand binding domain of human EPHB3.";
RL Submitted (JAN-2011) to the PDB data bank.
RN [8]
RP VARIANTS [LARGE SCALE ANALYSIS] LEU-168; CYS-440; VAL-579; LEU-601 AND
RP TRP-724.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Receptor tyrosine kinase which binds promiscuously
CC transmembrane ephrin-B family ligands residing on adjacent cells,
CC leading to contact-dependent bidirectional signaling into
CC neighboring cells. The signaling pathway downstream of the
CC receptor is referred to as forward signaling while the signaling
CC pathway downstream of the ephrin ligand is referred to as reverse
CC signaling. Generally has an overlapping and redundant function
CC with EPHB2. Like EPHB2, functions in axon guidance during
CC development regulating for instance the neurons forming the corpus
CC callosum and the anterior commissure, 2 major interhemispheric
CC connections between the temporal lobes of the cerebral cortex.
CC Beside its role in axon guidance plays also an important redundant
CC role with other ephrin-B receptors in development and maturation
CC of dendritic spines and the formation of excitatory synapses.
CC Controls other aspects of development through regulation of cell
CC migration and positioning. This includes angiogenesis, palate
CC development and thymic epithelium development for instance.
CC Forward and reverse signaling through the EFNB2/EPHB3 complex also
CC regulate migration and adhesion of cells that tubularize the
CC urethra and septate the cloaca. Finally, plays an important role
CC in intestinal epithelium differentiation segregating progenitor
CC from differentiated cells in the crypt.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- SUBUNIT: Heterotetramer upon binding of the ligand. The
CC heterotetramer is composed of an ephrin dimer and a receptor
CC dimer. Oligomerization is probably required to induce biological
CC responses (By similarity).
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Cell projection, dendrite (By similarity).
CC -!- TISSUE SPECIFICITY: Ubiquitous.
CC -!- PTM: Phosphorylated. Autophosphorylates upon ligand-binding.
CC Autophosphorylation on Tyr-614 is required for interaction with
CC SH2 domain-containing proteins.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. Ephrin receptor subfamily.
CC -!- SIMILARITY: Contains 1 Eph LBD (Eph ligand-binding) domain.
CC -!- SIMILARITY: Contains 2 fibronectin type-III domains.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 SAM (sterile alpha motif) domain.
CC -----------------------------------------------------------------------
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DR EMBL; X75208; CAA53021.1; -; mRNA.
DR EMBL; BC052968; AAH52968.1; -; mRNA.
DR PIR; S37627; S37627.
DR RefSeq; NP_004434.2; NM_004443.3.
DR UniGene; Hs.2913; -.
DR PDB; 3P1I; X-ray; 2.10 A; A/B/C=39-211.
DR PDBsum; 3P1I; -.
DR ProteinModelPortal; P54753; -.
DR SMR; P54753; 37-906, 922-992.
DR IntAct; P54753; 3.
DR MINT; MINT-1538099; -.
DR STRING; 9606.ENSP00000332118; -.
DR BindingDB; P54753; -.
DR ChEMBL; CHEMBL4901; -.
DR GuidetoPHARMACOLOGY; 1832; -.
DR PhosphoSite; P54753; -.
DR DMDM; 76803655; -.
DR PaxDb; P54753; -.
DR PRIDE; P54753; -.
DR DNASU; 2049; -.
DR Ensembl; ENST00000330394; ENSP00000332118; ENSG00000182580.
DR GeneID; 2049; -.
DR KEGG; hsa:2049; -.
DR UCSC; uc003foz.3; human.
DR CTD; 2049; -.
DR GeneCards; GC03P184279; -.
DR HGNC; HGNC:3394; EPHB3.
DR HPA; HPA007698; -.
DR HPA; HPA008184; -.
DR MIM; 601839; gene.
DR neXtProt; NX_P54753; -.
DR PharmGKB; PA27826; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233856; -.
DR HOVERGEN; HBG062180; -.
DR InParanoid; P54753; -.
DR KO; K05112; -.
DR OMA; LQQYITP; -.
DR OrthoDB; EOG7VTDM6; -.
DR PhylomeDB; P54753; -.
DR BRENDA; 2.7.10.1; 2681.
DR SignaLink; P54753; -.
DR EvolutionaryTrace; P54753; -.
DR GeneWiki; EPHB3; -.
DR GenomeRNAi; 2049; -.
DR NextBio; 8331; -.
DR PRO; PR:P54753; -.
DR ArrayExpress; P54753; -.
DR Bgee; P54753; -.
DR CleanEx; HS_EPHB3; -.
DR Genevestigator; P54753; -.
DR GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR GO; GO:0005887; C:integral to plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008046; F:axon guidance receptor activity; IEA:Ensembl.
DR GO; GO:0005003; F:ephrin receptor activity; IDA:UniProtKB.
DR GO; GO:0001525; P:angiogenesis; ISS:UniProtKB.
DR GO; GO:0007411; P:axon guidance; ISS:UniProtKB.
DR GO; GO:0007413; P:axonal fasciculation; ISS:UniProtKB.
DR GO; GO:0016477; P:cell migration; IDA:UniProtKB.
DR GO; GO:0021952; P:central nervous system projection neuron axonogenesis; IEA:Ensembl.
DR GO; GO:0022038; P:corpus callosum development; ISS:UniProtKB.
DR GO; GO:0060997; P:dendritic spine morphogenesis; ISS:UniProtKB.
DR GO; GO:0048546; P:digestive tract morphogenesis; ISS:UniProtKB.
DR GO; GO:0060021; P:palate development; ISS:UniProtKB.
DR GO; GO:0051965; P:positive regulation of synapse assembly; ISS:UniProtKB.
DR GO; GO:0046777; P:protein autophosphorylation; IDA:UniProtKB.
DR GO; GO:0050770; P:regulation of axonogenesis; ISS:UniProtKB.
DR GO; GO:0043088; P:regulation of Cdc42 GTPase activity; IDA:UniProtKB.
DR GO; GO:0022407; P:regulation of cell-cell adhesion; IDA:UniProtKB.
DR GO; GO:0032314; P:regulation of Rac GTPase activity; IDA:UniProtKB.
DR GO; GO:0031290; P:retinal ganglion cell axon guidance; IEA:Ensembl.
DR GO; GO:0034446; P:substrate adhesion-dependent cell spreading; IDA:UniProtKB.
DR GO; GO:0048538; P:thymus development; ISS:UniProtKB.
DR GO; GO:0001655; P:urogenital system development; ISS:UniProtKB.
DR Gene3D; 1.10.150.50; -; 1.
DR Gene3D; 2.60.120.260; -; 1.
DR Gene3D; 2.60.40.10; -; 2.
DR InterPro; IPR027936; Eph_TM.
DR InterPro; IPR001090; Ephrin_rcpt_lig-bd_dom.
DR InterPro; IPR003961; Fibronectin_type3.
DR InterPro; IPR008979; Galactose-bd-like.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001660; SAM.
DR InterPro; IPR013761; SAM/pointed.
DR InterPro; IPR021129; SAM_type1.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR011641; Tyr-kin_ephrin_A/B_rcpt-like.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR016257; Tyr_kinase_ephrin_rcpt.
DR InterPro; IPR001426; Tyr_kinase_rcpt_V_CS.
DR Pfam; PF14575; EphA2_TM; 1.
DR Pfam; PF01404; Ephrin_lbd; 1.
DR Pfam; PF00041; fn3; 2.
DR Pfam; PF07699; GCC2_GCC3; 1.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR Pfam; PF00536; SAM_1; 1.
DR PIRSF; PIRSF000666; TyrPK_ephrin_receptor; 1.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00615; EPH_lbd; 1.
DR SMART; SM00060; FN3; 2.
DR SMART; SM00454; SAM; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF47769; SSF47769; 1.
DR SUPFAM; SSF49265; SSF49265; 1.
DR SUPFAM; SSF49785; SSF49785; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS51550; EPH_LBD; 1.
DR PROSITE; PS50853; FN3; 2.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS00790; RECEPTOR_TYR_KIN_V_1; 1.
DR PROSITE; PS00791; RECEPTOR_TYR_KIN_V_2; 1.
DR PROSITE; PS50105; SAM_DOMAIN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Angiogenesis; ATP-binding; Cell membrane;
KW Cell projection; Complete proteome; Developmental protein;
KW Disulfide bond; Glycoprotein; Kinase; Membrane; Neurogenesis;
KW Nucleotide-binding; Phosphoprotein; Polymorphism; Receptor;
KW Reference proteome; Repeat; Signal; Transferase; Transmembrane;
KW Transmembrane helix; Tyrosine-protein kinase.
FT SIGNAL 1 33 Potential.
FT CHAIN 34 998 Ephrin type-B receptor 3.
FT /FTId=PRO_0000016831.
FT TOPO_DOM 34 559 Extracellular (Potential).
FT TRANSMEM 560 580 Helical; (Potential).
FT TOPO_DOM 581 998 Cytoplasmic (Potential).
FT DOMAIN 39 217 Eph LBD.
FT DOMAIN 339 451 Fibronectin type-III 1.
FT DOMAIN 452 545 Fibronectin type-III 2.
FT DOMAIN 633 896 Protein kinase.
FT DOMAIN 925 989 SAM.
FT NP_BIND 639 647 ATP (By similarity).
FT MOTIF 996 998 PDZ-binding (Potential).
FT COMPBIAS 199 336 Cys-rich.
FT ACT_SITE 758 758 Proton acceptor (By similarity).
FT BINDING 665 665 ATP (By similarity).
FT MOD_RES 614 614 Phosphotyrosine; by autocatalysis.
FT CARBOHYD 351 351 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 445 445 N-linked (GlcNAc...) (Potential).
FT DISULFID 81 199
FT VARIANT 168 168 R -> L (in a lung small cell carcinoma
FT sample; somatic mutation).
FT /FTId=VAR_042176.
FT VARIANT 440 440 R -> C (in dbSNP:rs56029711).
FT /FTId=VAR_042177.
FT VARIANT 579 579 I -> V (in dbSNP:rs56103851).
FT /FTId=VAR_042178.
FT VARIANT 601 601 I -> L (in dbSNP:rs56129875).
FT /FTId=VAR_042179.
FT VARIANT 724 724 R -> W (in a lung neuroendocrine
FT carcinoma sample; somatic mutation).
FT /FTId=VAR_042180.
FT MUTAGEN 614 614 Y->F: Partial loss of phosphorylation and
FT loss of interaction with SH2-containing
FT proteins.
FT MUTAGEN 665 665 K->R: Kinase-dead. Loss of
FT autophosphorylation.
FT CONFLICT 367 367 G -> V (in Ref. 1; CAA53021).
FT CONFLICT 406 408 TER -> SEP (in Ref. 1; CAA53021).
FT CONFLICT 412 412 I -> T (in Ref. 1; CAA53021).
FT STRAND 39 44
FT HELIX 45 47
FT STRAND 55 58
FT STRAND 63 68
FT STRAND 74 80
FT STRAND 85 87
FT STRAND 90 93
FT STRAND 103 114
FT HELIX 116 118
FT STRAND 130 139
FT STRAND 155 160
FT STRAND 175 181
FT STRAND 186 198
FT STRAND 200 210
SQ SEQUENCE 998 AA; 110330 MW; 9B65A4EF58B27407 CRC64;
MARARPPPPP SPPPGLLPLL PPLLLLPLLL LPAGCRALEE TLMDTKWVTS ELAWTSHPES
GWEEVSGYDE AMNPIRTYQV CNVRESSQNN WLRTGFIWRR DVQRVYVELK FTVRDCNSIP
NIPGSCKETF NLFYYEADSD VASASSPFWM ENPYVKVDTI APDESFSRLD AGRVNTKVRS
FGPLSKAGFY LAFQDQGACM SLISVRAFYK KCASTTAGFA LFPETLTGAE PTSLVIAPGT
CIPNAVEVSV PLKLYCNGDG EWMVPVGACT CATGHEPAAK ESQCRPCPPG SYKAKQGEGP
CLPCPPNSRT TSPAASICTC HNNFYRADSD SADSACTTVP SPPRGVISNV NETSLILEWS
EPRDLGGRDD LLYNVICKKC HGAGGASACS RCDDNVEFVP RQLGLTERRV HISHLLAHTR
YTFEVQAVNG VSGKSPLPPR YAAVNITTNQ AAPSEVPTLR LHSSSGSSLT LSWAPPERPN
GVILDYEMKY FEKSEGIAST VTSQMNSVQL DGLRPDARYV VQVRARTVAG YGQYSRPAEF
ETTSERGSGA QQLQEQLPLI VGSATAGLVF VVAVVVIAIV CLRKQRHGSD SEYTEKLQQY
IAPGMKVYID PFTYEDPNEA VREFAKEIDV SCVKIEEVIG AGEFGEVCRG RLKQPGRREV
FVAIKTLKVG YTERQRRDFL SEASIMGQFD HPNIIRLEGV VTKSRPVMIL TEFMENCALD
SFLRLNDGQF TVIQLVGMLR GIAAGMKYLS EMNYVHRDLA ARNILVNSNL VCKVSDFGLS
RFLEDDPSDP TYTSSLGGKI PIRWTAPEAI AYRKFTSASD VWSYGIVMWE VMSYGERPYW
DMSNQDVINA VEQDYRLPPP MDCPTALHQL MLDCWVRDRN LRPKFSQIVN TLDKLIRNAA
SLKVIASAQS GMSQPLLDRT VPDYTTFTTV GDWLDAIKMG RYKESFVSAG FASFDLVAQM
TAEDLLRIGV TLAGHQKKIL SSIQDMRLQM NQTLPVQV
//
MIM
601839
*RECORD*
*FIELD* NO
601839
*FIELD* TI
*601839 EPHRIN RECEPTOR EphB3; EPHB3
;;EPH-LIKE TYROSINE KINASE 2; ETK2;;
HUMAN EMBRYO KINASE 2; HEK2;;
read moreTYRO6
*FIELD* TX
See 179610 for background on Eph receptors and their ligands, the
ephrins.
CLONING
Bohme et al. (1993) used PCR to isolate a novel protein tyrosine kinase
(PTK), which they termed HEK2 for 'human embryo kinase-2,' from a human
embryonic cDNA library. Sequence analysis revealed that HEK2 encodes a
998-amino acid polypeptide having a single putative transmembrane
domain, a secretory signal sequence, and 2 fibronectin repeats. Based on
sequence homology, Bohme et al. (1993) stated that HEK2 is a member of
the EPH/ELK family of tyrosine kinases. Northern blot analysis revealed
that HEK2 was expressed as a variable 4.6-kb message in all adult human
tissues tested. Southern blot analysis suggested that HEK2 is a
single-copy gene in the human genome.
Ruiz et al. (1994) cloned the mouse ortholog of human HEK2. They found
that prior to and at the time of heart formation, 7.5 to 8.0 days
postcoitum (dpc), Hek2 is expressed in the cranial (rostral) region of
the embryo from which a subpopulation of cells gives rise to the
rudimentary heart. Between 8.0 and 9.5 dpc, Hek2 mRNA expression is
observed in myocardial cells, head mesenchyme, and paraxial mesoderm.
Hek2 transcripts are not detected in endocardial cells. After 9.5 dpc,
Hek2 expression is downregulated.
GENE FUNCTION
Bohme et al. (1996) presented evidence that HEK2 interacts with 2
ligands of EPH-related kinases (LERKs), namely, LERK2 (EFNB1; 300035)
and LERK5 (EFNB2; 600527). They reported that coincubation of HEK2- and
LERK2-expressing cells induces cell-cell adhesion and aggregation.
Additionally, coexpression of HEK2 and LERK2 results in reduced kinase
activity of HEK2.
Batlle et al. (2002) showed that beta-catenin (116806) and TCF (see
TCF7L2; 602228) inversely control the expression of the EphB2
(600997)/EphB3 receptors and their ligand, ephrin B1, in colorectal
cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3
genes revealed that their gene products restrict cell intermingling and
allocate cell populations within the intestinal epithelium. In
EphB2/EphB3 null mice, the proliferative and differentiated populations
intermingled. In adult EphB3 -/- mice, Paneth cells did not follow their
downward migratory path, but scattered along crypt and villus. The
authors concluded that, in the intestinal epithelium, beta-catenin and
TCF couple proliferation and differentiation to the sorting of cell
populations through the EphB/ephrin B system.
Benson et al. (2005) hypothesized that molecules that act as repellents
in vertebrate embryonic axonal pathfinding may also inhibit regeneration
after injury. By immunohistochemical and Western blot analyses, they
showed that Ephb3 was expressed in postnatal myelinating
oligodendrocytes of mouse spinal cord. Neurite outgrowth assays with
primary central nervous system neurons showed that Ephb3 possessed an
inhibitory activity equivalent to the p75 (NGFR; 162010)-mediated
activities of Nogo66 (RTN4; 604475), Mag (159460), and Omgp (OMG;
164345) combined. Benson et al. (2005) concluded that EPHB3 is a
myelin-based inhibitor of neurite outgrowth.
Using gain- and loss-of-function experiments in mice, Holmberg et al.
(2006) found that EphB receptors, in addition to directing cell
migration, regulated proliferation in the intestine. EphB2 and EphB3
kinase-dependent signaling promoted cell cycle reentry of intestinal
progenitor cells and accounted for about 50% of the mitogenic activity
in adult mouse small intestine and colon. Holmberg et al. (2006)
concluded EphB receptors are key coordinators of migration and
proliferation in the intestinal stem cell niche.
MAPPING
Bohme et al. (1993) used PCR of human-mouse hybrids to map the EPHB3
gene to human chromosome 3q21-qter.
ANIMAL MODEL
Halford et al. (2000) generated mice deficient in Ryk (600524) and found
that they had a distinctive craniofacial appearance, shortened limbs,
and postnatal mortality due to feeding and respiratory complications
associated with a complete cleft of the secondary palate. Consistent
with cleft palate phenocopy in Ephb2/Ephb3-deficient mice and the role
of a Drosophila Ryk ortholog, 'Derailed,' in the transduction of
repulsive axon pathfinding cues, biochemical data implicated Ryk in
signaling mediated by Eph receptors and cell junction-associated Af6
(159559). Halford et al. (2000) concluded that their findings
highlighted the importance of signal crosstalk between members of
different RTK subfamilies.
Alfaro et al. (2008) observed significantly reduced thymic cellularity
in both double-negative (DN; CD4 (186940)-negative/CD8 (see
186910)-negative) and double-positive cells in Ephb2- and/or
Ephb3-deficient mice. Adult mutant thymuses had increased proportions of
DN cells without significant variation in the percentage of other
subsets. Thymocyte number decreased significantly in all compartments
from the DN3 (CD44 (107269)-negative/CD25 (147730)-positive) stage
onward, without variation in the numbers of either DN1
(CD44-positive/CD25-negative) or DN2 (CD44-positive/CD25-positive)
cells. Alfaro et al. (2008) observed the same changes in day-15 fetal
Ephb2- and/or Ephb3-deficient thymi and proposed that the adult
phenotype results from the gradual accumulation of defects appearing
early in ontogeny.
*FIELD* RF
1. Alfaro, D.; Munoz, J. J.; Garcia-Ceca, J.; Cejalvo, T.; Jimenez,
E.; Zapata, A.: Alterations in the thymocyte phenotype of EphB-deficient
mice largely affect the double negative cell compartment. Immunology 125:
131-143, 2008.
2. Batlle, E.; Henderson, J. T.; Beghtel, H.; van den Born, M. M.
W.; Sancho, E.; Huls, G.; Meeldijk, J.; Robertson, J.; van de Wetering,
M.; Pawson, T.; Clevers, H.: Beta-catenin and TCF mediate cell positioning
in the intestinal epithelium by controlling the expression of EphB/EphrinB. Cell 111:
251-263, 2002.
3. Benson, M. D.; Romero, M. I.; Lush, M. E.; Lu, Q. R.; Henkemeyer,
M.; Parada, L. F.: Ephrin-B3 is a myelin-based inhibitor of neurite
outgrowth. Proc. Nat. Acad. Sci. 102: 10694-10699, 2005.
4. Bohme, B.; Holtrich, U.; Wolf, G.; Luzius, H.; Grzeschik, K.-H.;
Strebhardt, K.; Rubsamen-Waigmann, H.: PCR mediated detection of
a new human receptor-tyrosine-kinase, HEK 2. Oncogene 8: 2857-2862,
1993.
5. Bohme, B.; VandenBos, T.; Cerretti, D. P.; Park, L. S.; Holtrich,
U.; Rubsamen-Waigmann, H.; Strebhardt, K.: Cell-cell adhesion mediated
by binding of membrane-anchored ligand LERK-2 to the EPH-related receptor
human embryonal kinase 2 promotes tyrosine kinase activity. J. Biol.
Chem. 271: 24747-24752, 1996.
6. Halford, M. M.; Armes, J.; Buchert, M.; Meskenaite, V.; Grail,
D.; Hibbs, M. L.; Wilks, A. F.; Farlie, P. G.; Newgreen, D. F.; Hovens,
C. M.; Stacker, S. A.: Ryk-deficient mice exhibit craniofacial defects
associated with perturbed Eph receptor crosstalk. Nature Genet. 25:
414-418, 2000.
7. Holmberg, J.; Genander, M.; Halford, M. M.; Anneren, C.; Sondell,
M.; Chumley, M. J.; Silvany, R. E.; Henkemeyer, M.; Frisen, J.: EphB
receptors coordinate migration and proliferation in the intestinal
stem cell niche. Cell 125: 1151-1163, 2006.
8. Ruiz, J. C.; Conlon, F. L.; Robertson, E. J.: Identification of
novel protein kinases expressed in the myocardium of the developing
mouse heart. Mech. Dev. 48: 153-164, 1994.
*FIELD* CN
Matthew B. Gross - updated: 4/28/2010
Paul J. Converse - updated: 10/27/2009
Paul J. Converse - updated: 1/18/2007
Stylianos E. Antonarakis - updated: 12/3/2002
Carol A. Bocchini - updated: 2/28/2001
Ada Hamosh - updated: 8/1/2000
*FIELD* CD
Jennifer P. Macke: 5/29/1997
*FIELD* ED
wwang: 05/05/2010
mgross: 4/28/2010
mgross: 10/29/2009
terry: 10/27/2009
mgross: 1/18/2007
mgross: 12/3/2002
mcapotos: 3/1/2001
carol: 2/28/2001
alopez: 8/1/2000
psherman: 4/23/1998
psherman: 4/20/1998
dholmes: 1/20/1998
dholmes: 12/24/1997
alopez: 6/10/1997
alopez: 6/5/1997
*RECORD*
*FIELD* NO
601839
*FIELD* TI
*601839 EPHRIN RECEPTOR EphB3; EPHB3
;;EPH-LIKE TYROSINE KINASE 2; ETK2;;
HUMAN EMBRYO KINASE 2; HEK2;;
read moreTYRO6
*FIELD* TX
See 179610 for background on Eph receptors and their ligands, the
ephrins.
CLONING
Bohme et al. (1993) used PCR to isolate a novel protein tyrosine kinase
(PTK), which they termed HEK2 for 'human embryo kinase-2,' from a human
embryonic cDNA library. Sequence analysis revealed that HEK2 encodes a
998-amino acid polypeptide having a single putative transmembrane
domain, a secretory signal sequence, and 2 fibronectin repeats. Based on
sequence homology, Bohme et al. (1993) stated that HEK2 is a member of
the EPH/ELK family of tyrosine kinases. Northern blot analysis revealed
that HEK2 was expressed as a variable 4.6-kb message in all adult human
tissues tested. Southern blot analysis suggested that HEK2 is a
single-copy gene in the human genome.
Ruiz et al. (1994) cloned the mouse ortholog of human HEK2. They found
that prior to and at the time of heart formation, 7.5 to 8.0 days
postcoitum (dpc), Hek2 is expressed in the cranial (rostral) region of
the embryo from which a subpopulation of cells gives rise to the
rudimentary heart. Between 8.0 and 9.5 dpc, Hek2 mRNA expression is
observed in myocardial cells, head mesenchyme, and paraxial mesoderm.
Hek2 transcripts are not detected in endocardial cells. After 9.5 dpc,
Hek2 expression is downregulated.
GENE FUNCTION
Bohme et al. (1996) presented evidence that HEK2 interacts with 2
ligands of EPH-related kinases (LERKs), namely, LERK2 (EFNB1; 300035)
and LERK5 (EFNB2; 600527). They reported that coincubation of HEK2- and
LERK2-expressing cells induces cell-cell adhesion and aggregation.
Additionally, coexpression of HEK2 and LERK2 results in reduced kinase
activity of HEK2.
Batlle et al. (2002) showed that beta-catenin (116806) and TCF (see
TCF7L2; 602228) inversely control the expression of the EphB2
(600997)/EphB3 receptors and their ligand, ephrin B1, in colorectal
cancer and along the crypt-villus axis. Disruption of EphB2 and EphB3
genes revealed that their gene products restrict cell intermingling and
allocate cell populations within the intestinal epithelium. In
EphB2/EphB3 null mice, the proliferative and differentiated populations
intermingled. In adult EphB3 -/- mice, Paneth cells did not follow their
downward migratory path, but scattered along crypt and villus. The
authors concluded that, in the intestinal epithelium, beta-catenin and
TCF couple proliferation and differentiation to the sorting of cell
populations through the EphB/ephrin B system.
Benson et al. (2005) hypothesized that molecules that act as repellents
in vertebrate embryonic axonal pathfinding may also inhibit regeneration
after injury. By immunohistochemical and Western blot analyses, they
showed that Ephb3 was expressed in postnatal myelinating
oligodendrocytes of mouse spinal cord. Neurite outgrowth assays with
primary central nervous system neurons showed that Ephb3 possessed an
inhibitory activity equivalent to the p75 (NGFR; 162010)-mediated
activities of Nogo66 (RTN4; 604475), Mag (159460), and Omgp (OMG;
164345) combined. Benson et al. (2005) concluded that EPHB3 is a
myelin-based inhibitor of neurite outgrowth.
Using gain- and loss-of-function experiments in mice, Holmberg et al.
(2006) found that EphB receptors, in addition to directing cell
migration, regulated proliferation in the intestine. EphB2 and EphB3
kinase-dependent signaling promoted cell cycle reentry of intestinal
progenitor cells and accounted for about 50% of the mitogenic activity
in adult mouse small intestine and colon. Holmberg et al. (2006)
concluded EphB receptors are key coordinators of migration and
proliferation in the intestinal stem cell niche.
MAPPING
Bohme et al. (1993) used PCR of human-mouse hybrids to map the EPHB3
gene to human chromosome 3q21-qter.
ANIMAL MODEL
Halford et al. (2000) generated mice deficient in Ryk (600524) and found
that they had a distinctive craniofacial appearance, shortened limbs,
and postnatal mortality due to feeding and respiratory complications
associated with a complete cleft of the secondary palate. Consistent
with cleft palate phenocopy in Ephb2/Ephb3-deficient mice and the role
of a Drosophila Ryk ortholog, 'Derailed,' in the transduction of
repulsive axon pathfinding cues, biochemical data implicated Ryk in
signaling mediated by Eph receptors and cell junction-associated Af6
(159559). Halford et al. (2000) concluded that their findings
highlighted the importance of signal crosstalk between members of
different RTK subfamilies.
Alfaro et al. (2008) observed significantly reduced thymic cellularity
in both double-negative (DN; CD4 (186940)-negative/CD8 (see
186910)-negative) and double-positive cells in Ephb2- and/or
Ephb3-deficient mice. Adult mutant thymuses had increased proportions of
DN cells without significant variation in the percentage of other
subsets. Thymocyte number decreased significantly in all compartments
from the DN3 (CD44 (107269)-negative/CD25 (147730)-positive) stage
onward, without variation in the numbers of either DN1
(CD44-positive/CD25-negative) or DN2 (CD44-positive/CD25-positive)
cells. Alfaro et al. (2008) observed the same changes in day-15 fetal
Ephb2- and/or Ephb3-deficient thymi and proposed that the adult
phenotype results from the gradual accumulation of defects appearing
early in ontogeny.
*FIELD* RF
1. Alfaro, D.; Munoz, J. J.; Garcia-Ceca, J.; Cejalvo, T.; Jimenez,
E.; Zapata, A.: Alterations in the thymocyte phenotype of EphB-deficient
mice largely affect the double negative cell compartment. Immunology 125:
131-143, 2008.
2. Batlle, E.; Henderson, J. T.; Beghtel, H.; van den Born, M. M.
W.; Sancho, E.; Huls, G.; Meeldijk, J.; Robertson, J.; van de Wetering,
M.; Pawson, T.; Clevers, H.: Beta-catenin and TCF mediate cell positioning
in the intestinal epithelium by controlling the expression of EphB/EphrinB. Cell 111:
251-263, 2002.
3. Benson, M. D.; Romero, M. I.; Lush, M. E.; Lu, Q. R.; Henkemeyer,
M.; Parada, L. F.: Ephrin-B3 is a myelin-based inhibitor of neurite
outgrowth. Proc. Nat. Acad. Sci. 102: 10694-10699, 2005.
4. Bohme, B.; Holtrich, U.; Wolf, G.; Luzius, H.; Grzeschik, K.-H.;
Strebhardt, K.; Rubsamen-Waigmann, H.: PCR mediated detection of
a new human receptor-tyrosine-kinase, HEK 2. Oncogene 8: 2857-2862,
1993.
5. Bohme, B.; VandenBos, T.; Cerretti, D. P.; Park, L. S.; Holtrich,
U.; Rubsamen-Waigmann, H.; Strebhardt, K.: Cell-cell adhesion mediated
by binding of membrane-anchored ligand LERK-2 to the EPH-related receptor
human embryonal kinase 2 promotes tyrosine kinase activity. J. Biol.
Chem. 271: 24747-24752, 1996.
6. Halford, M. M.; Armes, J.; Buchert, M.; Meskenaite, V.; Grail,
D.; Hibbs, M. L.; Wilks, A. F.; Farlie, P. G.; Newgreen, D. F.; Hovens,
C. M.; Stacker, S. A.: Ryk-deficient mice exhibit craniofacial defects
associated with perturbed Eph receptor crosstalk. Nature Genet. 25:
414-418, 2000.
7. Holmberg, J.; Genander, M.; Halford, M. M.; Anneren, C.; Sondell,
M.; Chumley, M. J.; Silvany, R. E.; Henkemeyer, M.; Frisen, J.: EphB
receptors coordinate migration and proliferation in the intestinal
stem cell niche. Cell 125: 1151-1163, 2006.
8. Ruiz, J. C.; Conlon, F. L.; Robertson, E. J.: Identification of
novel protein kinases expressed in the myocardium of the developing
mouse heart. Mech. Dev. 48: 153-164, 1994.
*FIELD* CN
Matthew B. Gross - updated: 4/28/2010
Paul J. Converse - updated: 10/27/2009
Paul J. Converse - updated: 1/18/2007
Stylianos E. Antonarakis - updated: 12/3/2002
Carol A. Bocchini - updated: 2/28/2001
Ada Hamosh - updated: 8/1/2000
*FIELD* CD
Jennifer P. Macke: 5/29/1997
*FIELD* ED
wwang: 05/05/2010
mgross: 4/28/2010
mgross: 10/29/2009
terry: 10/27/2009
mgross: 1/18/2007
mgross: 12/3/2002
mcapotos: 3/1/2001
carol: 2/28/2001
alopez: 8/1/2000
psherman: 4/23/1998
psherman: 4/20/1998
dholmes: 1/20/1998
dholmes: 12/24/1997
alopez: 6/10/1997
alopez: 6/5/1997