Alternative titles; symbols
HGNC Approved Gene Symbol: EPHB2
Cytogenetic location: 1p36.12 Genomic coordinates (GRCh38): 1:22,710,838-22,921,500 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.12 | ?Bleeding disorder, platelet-type, 22 | 618462 | Autosomal recessive | 3 |
| {Prostate cancer/brain cancer susceptibility, somatic} | 603688 | 3 |
The EPHB2 gene encodes a transmembrane tyrosine kinase receptor. It is present in platelets, where it plays a role in cytoplasmic signaling causing platelet aggregation and activation. The ligand for this receptor is ephrin-B1 (EFNB1; 300035).
EPHB2 has a role both in cell-to-cell contact through bidirectional signaling, and in the absence of cell-to-cell contact, which may contribute to initial platelet activation signals. The cytoplasmic domain of EPHB2 has a role in the regulation of alpha-IIb (ITGA2B; 607759)/beta-3 (ITGB3; 173470) integrin signaling in platelets (summary by Vaiyapuri et al., 2015).
Chan and Watt (1991) cloned partial sequences of the EEK (EPHA8; 176945) and ERK genes encoding members of the EPH subclass of receptor protein-tyrosine kinases. Northern blot analysis of rat RNA showed that DNA encoding human ERK hybridized to transcripts most abundantly in lung.
By screening a human fetal brain cDNA expression library using a monoclonal antiphosphotyrosine antibody and by 5-prime RACE (rapid amplification of cDNA ends) procedures, Ikegaki et al. (1995) isolated overlapping cDNAs encoding a receptor-type tyrosine kinase belonging to the EPH family and designated the gene DRT (for developmentally regulated EPH-related tyrosine kinase). The DRT gene is expressed in transcripts of 3 different sizes (4, 5, and 11 kb). The DRT transcripts are expressed in human brain and several other tissues, including heart, lung, kidney, placenta, pancreas, liver, and skeletal muscle, but the 11-kb DRT transcript is preferentially expressed in fetal brain. Steady-state levels of DRT mRNA in several tissues, including brain, heart, lung, and kidney, are greater in the midterm fetus than those in the adult. Ikegaki et al. (1995) showed that a large number of tumor cell lines derived from neuroectoderm express DRT transcripts. The authors speculated that DRT may play a part in human neurogenesis.
Northern blot analysis by Fox et al. (1995) revealed that HEK5 is expressed as transcripts of several sizes in a variety of human tissues, with the highest level of expression in placenta.
Saito et al. (1995) demonstrated from the cDNA sequence that the ERK protein has a highly hydrophobic portion upstream of the putative tyrosine kinase domain, suggesting that it possesses a receptor-like membrane-spanning structure.
Using immunohistochemical analysis of the developing mouse hindbrain, Cowan et al. (2000) detected Ephb2 expression in the midline, including the floor plate and the ependymal layer.
Chan and Watt (1991) mapped the EEK and ERK genes to chromosome 1 by Southern blot analysis of somatic cell hybrids. Ikegaki et al. (1995) mapped DRT, the EPHB2 gene, to 1p36.1-p35 by PCR screening of human/rodent somatic cell hybrid panels and by fluorescence in situ hybridization. As the distal end of 1p is often deleted in neuroblastomas, the DRT gene may play a role in neuroblastoma and small cell lung carcinoma (SCLC) tumorigenesis.
By fluorescence in situ hybridization, Saito et al. (1995) demonstrated that the ERK gene is located in chromosomal region 1p36.1. They showed that the homologous genes are located on mouse 4D2.2-D3 and rat 5q36.13, both of which are regions with conserved linkage homology to human chromosome 1p.
Using a yeast 2-hybrid system, Cowan et al. (2000) demonstrated that PDZ domain-containing protein Pick1 (PRKCABP; 605926) binds the C-terminal tail of EphB2. Using colocalization studies and biochemical analysis, they demonstrated that a protein complex containing EphB2 and aquaporin-1 (AQP1; 107776) is formed in vivo. They concluded that Ephb2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water.
By treating embryonic rat cortical neurons with Efnb2 (600527), followed by stimulation with glutamate, Takasu et al. (2002) observed a large increase in intracellular calcium that was dependent on the cytoplasmic domain of the ephrin receptor Ephb2. Treatment with Bdnf (113505) did not result in an increase in glutamate-stimulated intracellular calcium. Western blot analysis showed that Efnb2 treatment increased tyrosine phosphorylation of NMDA receptor 2B (Nr2b, or Grin2b; 138252) at positions 1252, 1336, and 1472 by the Src family tyrosine kinase Fyn (137025). Efnb2 treatment also increased phosphorylation of Creb (123810) at ser133, which was mediated by the NMDA receptor. In addition, Efnb2 treatment potentiated glutamate activation of Bdnf and Cpg15. Takasu et al. (2002) concluded that the EFNB-EPHB-NMDA receptor interaction may represent an early step in the initiation of synapse formation or maturation and may potentiate the ability of the NMDA receptor to respond to activity-dependent signals from the extracellular milieu. In a perspective, Ghosh (2002) noted that Grunwald et al. (2001) and Henderson et al. (2001) reported that mice lacking Ephb2 had defective synaptic plasticity, particularly at CA1 synapses, possibly due to a lack of proper clustering of NMDA receptors at the synapse.
Murai and Pasquale (2002) reviewed evidence that Eph receptors function in modifying the strength of existing synapses in the adult brain.
Morphologic changes in dendritic spines are believed to be caused by dynamic regulation of actin polymerization. Irie and Yamaguchi (2002) found that the EphB2 receptor tyrosine kinase physically associates with the guanine nucleotide exchange factor intersectin-1 (602442) in cooperation with the actin-regulating protein N-WASP (605056), which in turn activates the Rho family GTPase Cdc42 (116952) and spine morphogenesis.
EPHB receptor tyrosine kinases are involved in formation and remodeling of dendritic spines, which receive the majority of excitatory synaptic inputs in the brain. Using immunoprecipitation, Western blot, and immunocytochemical analyses Tolias et al. (2007) showed that the PH domain, coiled-coil domain, and an adjacent region of TIAM1 (600687) interacted with EPHB2. The interaction led to phosphorylation and recruitment of TIAM1 to EPHB complexes containing NMDA glutamate receptors. Mutation and RNA interference analyses revealed that disruption of TIAM1 function blocked EPHB2-induced spine formation. Tolias et al. (2007) proposed that EPHB receptors regulate spine development, in part, by recruiting and activating TIAM1, which leads to RAC1 (602048)-dependent actin remodeling required for spine formation.
Batlle et al. (2002) showed that beta-catenin (CTNNB1; 116806) and TCF (see TCF7L2; 602228) inversely control the expression of the EphB2/EphB3 (601839) receptors and their ligand, ephrin B1 (EFNB1; 300035), 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.
Himanen et al. (2004) found that ephrin-A5 (601535) binds to the EphB2 receptor, leading to receptor clustering, autophosphorylation, and initiation of downstream signaling. Ephrin-A5 induced EphB2-mediated growth cone collapse and neurite retraction in a model system. X-ray crystallography confirmed the interaction and showed that the ephrin-A5-EphB2 complex is a heterodimer. Himanen et al. (2004) emphasized the unexpected finding of crosstalk between A- and B-subclass Eph receptors and ephrins.
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.
The EPHB2 and EPHB3 genes are targets of beta-catenin and TCF4 (602272) in colorectal cancer (CRC; 114500) and in normal intestinal cells. In the intestinal epithelium, ephrin-B signaling controls the positioning of cell types along the crypt-villus axis. In CRC, ephrin-B activity suppresses tumor progression beyond the earliest stages. Cortina et al. (2007) showed that EphB receptors compartmentalize the expansion of CRC cells through a mechanism depending on adhesion mediated by E-caderin (CDH1; 192090). They demonstrated that EphB-mediated compartmentalization restricts the spreading of EphB-expressing tumor cells into ephrin-B1-positive territories in vitro and in vivo. At the onset of tumorigenesis, CRC cells must silence EphB expression to avoid repulsive interactions imposed by intestinal cells normally expressing ephrin-B1 (300035).
Jorgensen et al. (2009) implemented a proteomic strategy to systematically determine cell-specific signaling networks underlying EphB2- and ephrin-B1-controlled cell sorting. Quantitative mass spectrometric analysis of mixed populations of EphB2- and ephrin-B1-expressing cells that were labeled with different isotopes revealed cell-specific tyrosine phosphorylation events. Functional associations between these phosphotyrosine signaling networks and cell sorting were established with small interfering RNA screening. Data-driven network modeling revealed that signaling between mixed EphB2- and ephrin-B1-expressing cells is asymmetric and that the distinct cell types use different tyrosine kinases and targets to process signals induced by cell-cell contact. Jorgensen et al. (2009) provided systems- and cell-specific network models of contact-initiated signaling between 2 distinct cell types.
Cisse et al. (2011) showed that amyloid-beta (see 104760) oligomers bind to the fibronectin repeat domain of EphB2 and trigger EphB2 degradation in the proteasome. To determine the pathogenic importance of EphB2 depletions in Alzheimer disease and related models, they used lentiviral constructs to reduce or increase neuronal expression of EphB2 in memory centers of the mouse brain. In nontransgenic mice, knockdown of EphB2 mediated by short hairpin RNA reduced NMDA receptor currents and impaired long-term potentiation, important for memory formation, in the dentate gyrus. Increasing EphB2 expression in the dentate gyrus of human amyloid precursor protein transgenic mice reversed deficits in NMDA receptor-dependent long-term potentiation and memory impairments. Thus, Cisse et al. (2011) concluded that depletion of EphB2 is critical in amyloid-beta-induced neuronal dysfunction, and suggests that increasing EphB2 levels or function could be beneficial in Alzheimer disease.
Margolis et al. (2010) showed that the mouse Rhoa (165390) guanine nucleotide exchange factor ephexin-5 (E5, or ARHGEF15; 608504) specifically coimmunoprecipitated with Ephb2. Knockdown and overexpression studies revealed that binding of E5 to Ephb2 inhibited formation of excitatory synapses. The E5-Ephb2 interaction was terminated by the binding of ephrin B to Ephb2. Activation of Ephb2 by ephrin B resulted in tyrosine phosphorylation, release, and destabilization of E5, permitting formation of additional excitatory synapses.
Attwood et al. (2011) demonstrated in mice that the serine protease neuropsin (605644) is critical for stress-related plasticity in the amygdala by regulating the dynamics of the EphB2-NMDA receptor interaction, the expression of Fkbp5 (602623), and anxiety-like behavior. Stress results in neuropsin-dependent cleavage of EphB2 in the amygdala, causing dissociation of EphB2 from the NR1 (138249) subunit of the NMDA receptor and promoting membrane turnover of EphB2 receptors. Dynamic EphB2-NR1 interaction enhances NMDA receptor current, induces Fkpb5 gene expression, and enhances behavioral signatures of anxiety. On stress, neuropsin-deficient mice do not show EphB2 cleavage and its dissociation from NR1, resulting in a static EphB2-NR1 interaction, attenuated induction of the Fkbp5 gene, and low anxiety. The behavioral response to stress can be restored by intraamygdala injection of neuropsin into neuropsin-deficient mice and disrupted by the injection of either anti-EphB2 antibodies or silencing the Fkbp5 gene in the amygdala of wildtype mice. Attwood et al. (2011) concluded that their findings established a novel neuronal pathway linking stress-induced proteolysis of EphB2 in the amygdala to anxiety.
Crystal Structure
Wybenga-Groot et al. (2001) reported the x-ray crystal structure of an autoinhibited, unphosphorylated form of EphB2 composed of the juxtamembrane region and the kinase domain at 1.9-angstrom resolution. The structure, supported by mutagenesis data, revealed that the juxtamembrane segment adopts a helical conformation that distorts the small lobe of the kinase domain and blocks the activation segment from attaining an activated conformation. Wybenga-Groot et al. (2001) stated that phosphorylation of conserved juxtamembrane tyrosines would relieve this autoinhibition by disturbing the association of the juxtamembrane segment with the kinase domain, while liberating phosphotyrosine sites for binding SH2 domains of target proteins.
EPHB receptors bind to and are activated by the transmembrane B-ephrins, resulting in the formation of discrete bidirectional signaling centers in which the EPH receptor tyrosine kinase domain transduces the forward signal into its cell and the ephrin transduces the reverse signal into its cell. Himanen et al. (2001) reported the crystal structure of the N-terminal ligand-binding globular domain of EPHB2 bound to the complete extracellular domain of EFNB2 at 2.7-angstrom resolution. The overall structure of each molecule in the complex is similar to that seen in the unbound molecule. Binding occurs through an expansive dimerization interface dominated by the insertion of an extended ephrin loop into a channel at the surface of the receptor. The EPHB-EFNB dimers then join to form a stable tetramer in which each molecule interacts with 2 complementary molecules, allowing transautophosphorylation and signal initiation.
Platelet-type Bleeding Disorder 22
In 2 sibs, born of consanguineous parents, with platelet-type bleeding disorder-22 (BDPLT22; 618462), Berrou et al. (2018) identified a homozygous missense mutation in the EPHB2 gene (R745C; 600997.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional analysis of patient platelets showed strongly impaired platelet aggregation in response to ADP and thrombin, with decreased thrombus formation, as well as partially impaired granule secretion. There was an absence of activation of the platelet integrin IIb (607759)/IIIa (173470) receptor. Response to ristocetin was normal, and the platelets had normal levels of alpha and dense granules. Overexpression of wildtype and the R745C EPHB2 variant in rat basophilic leukemia cells stably expressing human glycoprotein VI (GPVI; 605546) confirmed that the EPHB2 R745C mutation impaired EPHB2 autophosphorylation. However, it had no effect on ephrin ligand-induced EPHB2 clustering, suggesting it did not interfere with EPHB2-ephrin-mediated cell-to-cell contact. Overall, the findings indicated that the EPHB2 variant impaired activation of the GP VI receptor and downstream signaling of the IIb/IIIa receptor.
Somatic Mutations
Huusko et al. (2004) combined emetine inhibition of nonsense-mediated decay (NMD) and microarray analysis with comparative genomic hybridization (CGH) to screen prostate cancer-derived cell lines for transcripts that undergo NMD and are transcribed from genes with deletions on both alleles. This way they could identify genes with inactivation of the 1 allele by a nonsense mutation and loss of the outer allele through deletion. They identified previously unknown mutations in the EPHB2 gene. The DU 145 prostate cancer cell line, originating from a brain metastasis, was found to carry a truncating mutation of EPHB2 (600997.0001) and a deletion of the remaining allele. Additional frameshift, splice site, missense, and nonsense mutations were present in clinical prostate cancer samples. Transfection of DU 145 cells, which lack functional EPHB2, with wildtype EPHB2 suppressed clonogenic growth. These studies indicated that EPHB2 may have an essential role in cell migration and maintenance of normal tissue architecture and that mutational inactivation of the EPHB2 gene may be important in the progression and metastasis of prostate cancer. Mercola and Welsh (2004) reviewed the combination of methods, emetine suppression of NMD and microarray analysis with CGH, for identifying disease-gene associations. As many as one-third of inherited disorders are caused by mutations that disrupt reading frames.
Kittles et al. (2006) performed direct sequencing of the coding region of EPHB2 in 72 probands from the African American Hereditary Prostate Cancer Study. They found the K1019X (3055A-T; 600997.0004) mutation in 15.3% of the African American probands but in only 1.7% of 231 European American control samples. The T allele was significantly more common among African American probands (15.3%) than among African American male controls (5.2%) (odds ratio = 3.31). In order to rule out a spurious association of K1019X with prostate cancer in African Americans due to admixture stratification, Kittles et al. (2006) controlled for ancestral differences between prostate cancer cases and controls by estimating individual ancestry for each subject using 34 ancestry-informative markers (AIMs). Individual West African ancestry ranged from 10% to 93.5% with a mean estimate of 71.3%. The estimates for West African ancestry for the controls ranged from 6.5% to 95.3%. After testing for individual ancestry, the association of EPHB2 K10X probands compared with African American healthy controls was still significant (p = 0.01).
Johnson et al. (2010) identified subgroups of human ependymoma (137800) and then performed genomic analyses and found subgroup-specific alterations that included amplifications and homozygous deletions of genes not previously implicated in ependymoma. They then used cross-species genomics to select cellular compartments most likely to give rise to subgroups of ependymoma and compared human tumors and mouse neural stem cells, isolated from different regions, specifically with an intact or deleted Cdkn2a (600160)/Cdkn2b (600431) locus. The transcriptome of human supratentorial ependymomas with amplified EPHB2 and deleted CDKN2A/CDKN2B matched only that of embryonic cerebral Cdkn2a/Cdkn2b -/- mouse neuronal stem cells. Activation of Ephb2 signaling in Cdkn2a/Cdkn2b -/- mouse neuronal stem cells, but not other neural stem cells, generated the first mouse model of ependymoma, which was highly penetrant and accurately modeled the histology and transcriptome of 1 subgroup of human supratentorial tumor (subgroup D). Comparative analysis of matched mouse and human tumors revealed selective deregulation in the expression and copy number of genes that control synaptogenesis, pinpointing disruption of this pathway as a critical event in the production of this ependymoma subgroup.
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.
Henkemeyer et al. (1996) generated 2 different lines of mice lacking Ephb2, which they called Nuk1: a null allele and an allele that encodes a beta-gal fusion receptor lacking the tyrosine kinase and C-terminal domains. By analyzing brains from homozygous mutant mice, they demonstrated that the majority of axons forming the posterior tract of the anterior commissure migrate aberrantly to the floor of the brain, resulting in a failure of cortical neurons to link the 2 temporal lobes. Henkemeyer et al. (1996) concluded that Ephb2, a receptor that binds transmembrane ligands, plays a critical and unique role in the pathfinding of specific axons in the mammalian central nervous system.
Cowan et al. (2000) detected a strain-specific circling behavior associated with abnormal vestibular function in the Ephb2 knockout mutant mice generated by Henkemeyer et al. (1996). In mutant embryos, the contralateral inner ear efferent growth cones exhibited inappropriate pathway selection at the midline, while in mutant adults, the endolymph-filled lumen of the semicircular canals was severely reduced. EphB2 is expressed in the endolymph-producing dark cells in the inner ear epithelium, and these cells showed ultrastructural defects in the mutants. A molecular link to fluid regulation was provided by the demonstration that PDZ domain-containing proteins that bind the C termini of EphB2 and B-ephrins can also recognize the cytoplasmic tails of anion exchangers and aquaporins. Cowan et al. (2000) suggested that EphB2 may regulate ionic homeostasis and endolymph fluid production through macromolecular associations with membrane channels that transport chloride, bicarbonate, and water.
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.
Vaiyapuri et al. (2015) found expression of the Ephb2 gene in mouse platelets and demonstrated that Ephb2 has a complex role in platelet activation involving both contact-dependent and contact-independent signaling. Functional studies of platelets from mice with Ephb2 lacking the intracellular region (LacZ mutants) showed that interruption of the intracellular region abrogated platelet activation, granule secretion, calcium mobilization, fibrinogen binding, and thrombus formation. These functional defects were associated with reduced inside-out signaling through PI3K and platelet integrin ITGA2B/ITGB3. Defective spreading and clot retraction in mutant platelets suggested that Ephb2 may also be involved in outside-in signaling when fibrinogen binds to ITGA2B/ITGB3. These changes occurred even though ligand binding of Ephb2 at the platelet surface was unaffected. Mutant mice showed increased bleeding.
In the prostate cancer (603688) cell line DU 145, derived from a brain metastasis, Huusko et al. (2004) used a combination of nonsense-mediated RNA decay microarrays and array-based comparative genomic hybridization for identification of biallelic inactivation of the EPHB2 gene involving loss of the wildtype allele and a nonsense gln723-to-ter (Q723X) mutation in the other allele. The Q723X substitution arose from a 2167C-T transition.
In a metastatic prostate cancer (603688) sample, Huusko et al. (2004) discovered a heterozygous ala279-to-ser (A279S) mutation that resulted from an 835G-T transversion in the EPHB2 gene. The other allele was lost.
In 2 primary prostate cancers (603688), Huusko et al. (2004) found an asp679-to-asn (D679N) mutation that resulted from a 2035G-A transition in the EPHB2 gene. The wildtype allele was not lost. The mutation was not found in any of 246 normal controls.
Kittles et al. (2006) demonstrated association between a nonsense mutation, lys1019 to stop (K1019X), in the EPHB2 gene and prostate cancer (603688) in African Americans. The K1019X substitution arises from a 3055A-T transversion in exon 15.
In 2 sibs, born of consanguineous parents, with platelet-type bleeding disorder-22 (BDPLT22; 618462), Berrou et al. (2018) identified a homozygous c.2233C-T transition (c.2233C-T, NM_004442.6) in the EPHB2 gene, resulting in an arg745-to-cys (R745C) substitution at a conserved residue in the intracytoplasmic tyrosine kinase domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found at a very low frequency (less than 10(-6)) in the ExAC database.
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