Abstract
Eph receptors constitute the largest subfamily of receptor tyrosine kinases and mediate contact-dependent cell–cell communication in many tissues. Unique features of Eph receptors include their engagement with membrane-attached ephrin ligands, the requirement of higher-order clustering for full activation, and bidirectional signaling into the receptor- as well as ligand-expressing cell. Eph receptor functions can be additionally modulated by cis interactions with ephrins expressed on the same cell as well as proteolytic cleavage. Extensive studies in several model organisms have implicated Eph receptors in multiple physiological and pathological processes at all stages from early embryogenesis to aging. Eph signaling is often repulsive and governs cell sorting, migration, and boundary formation. During embryonic and early postnatal period, Ephs are involved in the development of the nervous system, cardiovascular system, and several other organs and tissues. Eph receptors also have various functions in adult physiology, including their important role in neural plasticity. Finally, Ephs have emerged as important players in different types of cancer and several neurological diseases and are regarded as potential drug targets for these disorders.
In this chapter, we describe the common features and functions of Eph receptors and provide specific information on the individual family members.
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- 1.
UniProt (http://www.uniprot.org).
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Phosphosite (http://www.phosphosite.org).
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Elowe S, Holland SJ, Kulkarni S, Pawson T. Downregulation of the Ras-mitogen-activated protein kinase pathway by the EphB2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. Mol Cell Biol. 2001;21(21):7429–41.
Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, et al. Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell. 2009;139(4):679–92.
Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol. 2005;6(6):462–75.
Darie CC, Deinhardt K, Zhang G, Cardasis HS, Chao MV, Neubert TA. Identifying transient protein-protein interactions in EphB2 signaling by Blue Native PAGE and Mass Spectrometry. Proteomics. 2011;11:4514–28.
Shi Y, Pontrello CG, DeFea KA, Reichardt LF, Ethell IM. Focal adhesion kinase acts downstream of EphB receptors to maintain mature dendritic spines by regulating cofilin activity. J Neurosci. 2009;29(25):8129–42.
Hoogenraad CC, Milstein AD, Ethell IM, Henkemeyer M, Sheng M. GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking. Nat Neurosci. 2005;8(7):906–15.
Tanaka M, Kamo T, Ota S, Sugimura H. Association of Dishevelled with Eph tyrosine kinase receptor and ephrin mediates cell repulsion. EMBO J. 2003;22(4):847–58.
Marston DJ, Dickinson S, Nobes CD. Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion. Nat Cell Biol. 2003;5(10):879–88.
Altick AL, Dravis C, Bowdler T, Henkemeyer M, Mastick GS. EphB receptor tyrosine kinases control morphological development of the ventral midbrain. Mech Dev. 2005;122(4):501–12.
Garcia-Ceca J, Jimenez E, Alfaro D, Cejalvo T, Munoz JJ, Zapata AG. Cell-autonomous role of EphB2 and EphB3 receptors in the thymic epithelial cell organization. Eur J Immunol. 2009;39(10):2916–24.
van der Flier LG, van Gijn ME, Hatzis P, Kujala P, Haegebarth A, Stange DE, et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell. 2009;136(5):903–12.
Wu Q, Lind GE, Aasheim HC, Micci F, Silins I, Trope CG, et al. The EPH receptor Bs (EPHBs) promoters are unmethylated in colon and ovarian cancers. Epigenetics. 2007;2(4):237–43.
Hock B, Bohme B, Karn T, Feller S, Rubsamen-Waigmann H, Strebhardt K. Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. Oncogene. 1998;17(2):255–60.
Hock B, Bohme B, Karn T, Yamamoto T, Kaibuchi K, Holtrich U, et al. PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor. Proc Natl Acad Sci USA. 1998;95(17):9779–84.
Solanas G, Cortina C, Sevillano M, Batlle E. Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol. 2011;13(9):1100–7.
Miao H, Strebhardt K, Pasquale EB, Shen TL, Guan JL, Wang B. 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. J Biol Chem. 2005;280(2):923–32.
Maddigan A, Truitt L, Arsenault R, Freywald T, Allonby O, Dean J, et al. EphB receptors trigger Akt activation and suppress Fas receptor-induced apoptosis in malignant T lymphocytes. J Immunol. 2011;187(11):5983–94.
Zhuang Z, Yang B, Theus MH, Sick JT, Bethea JR, Sick TJ, et al. EphrinBs regulate D-serine synthesis and release in astrocytes. J Neurosci. 2010;30(47):16015–24.
Kamitori K, Tanaka M, Okuno-Hirasawa T, Kohsaka S. Receptor related to tyrosine kinase RYK regulates cell migration during cortical development. Biochem Biophys Res Commun. 2005;330(2):446–53.
Risley M, Garrod D, Henkemeyer M, McLean W. EphB2 and EphB3 forward signalling are required for palate development. Mech Dev. 2009;126(3–4):230–9.
Chrencik JE, Brooun A, Kraus ML, Recht MI, Kolatkar AR, Han GW, et al. Structural and biophysical characterization of the EphB4*ephrinB2 protein-protein interaction and receptor specificity. J Biol Chem. 2006;281(38):28185–92.
Steinle JJ, Meininger CJ, Forough R, Wu G, Wu MH, Granger HJ. Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem. 2002;277(46):43830–5.
Yu J, Bulk E, Ji P, Hascher A, Tang M, Metzger R, et al. The EPHB6 receptor tyrosine kinase is a metastasis suppressor that is frequently silenced by promoter DNA hypermethylation in non-small cell lung cancer. Clin Cancer Res. 2010;16(8):2275–83.
Matsuoka H, Obama H, Kelly ML, Matsui T, Nakamoto M. Biphasic functions of the kinase-defective Ephb6 receptor in cell adhesion and migration. J Biol Chem. 2005;280(32):29355–63.
Freywald A, Sharfe N, Rashotte C, Grunberger T, Roifman CM. The EphB6 receptor inhibits JNK activation in T lymphocytes and modulates T cell receptor-mediated responses. J Biol Chem. 2003;278(12):10150–6.
Allonby O, El Zawily AM, Freywald T, Mousseau DD, Chlan J, Anderson D, et al. Ligand stimulation induces clathrin- and Rab5-dependent downregulation of the kinase-dead EphB6 receptor preceded by the disruption of EphB6-Hsp90 interaction. Cell Signal. 2014;26(12):2645–57.
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Receptor at a glance: EphA1
Receptor at a glance: EphA1
Chromosome location | Human: chromosome 7: 143,087,382–143,105,985; reverse strand Mouse: chromosome 6: 42,308,486–42,323,267; reverse stranda |
Gene size (bp) | Human: 18,604. Mouse: 14,782a |
Intron/exon numbers | 18 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—3,363; 5′ UTR—87; ORF—2,931; 3′UTR—345 Mouse: mRNA—3,273; 5′ UTR—58; ORF—2,934; 3′UTR—281a |
Amino acid number | Human: 976. Mouse: 977b |
kDa | Human: 108. Mouse: 109b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | Ephrin-A1, −A3, −A4 |
Known dimerizing partners | EphA1 |
Pathways regulated | Inhibits Integrin-linked kinase; stimulates RhoA/ROCK |
Tissues expressed | Adult: epithelial tissue elements including those found in skin, kidney, ureter, uterus, vagina [299] |
Human Diseases | Risk locus for late-onset Alzheimer disease |
Knockout Mouse phenotype | Highly penetrant kinky-tail phenotype due to the deformation of the most caudal tail structures, and reminiscent of the EphA2 knockout phenotype; partially penetrant failure in the process of uterovaginal canalization dependent on a pro-apoptotic mechanism [299] |
Receptor at a glance: EphA2
Chromosome location | Human: chromosome 1: 16,450,832–16,482,582; reverse strand Mouse: chromosome 4: 140,857,155–140,885,299; forward stranda |
Gene size (bp) | Human: 31,751. Mouse: 28,145a |
Intron/exon numbers | 17 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—3,964; 5′ UTR—155; ORF—2,931; 3′UTR—878 Mouse: mRNA—3,913; 5′ UTR—113; ORF—2,934; 3′UTR—866a |
Amino acid number | Human: 976. Mouse: 977b |
kDa | Human: 108. Mouse: 109b |
Posttranslational modifications | Tyrosine phosphorylation, serine/threonine phosphorylation, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | EphrinA1 (preferred ligand), −A2, −A3, −A4, −A5 |
Known dimerizing partners | EphA2 |
Pathways regulated | Activates Rac1 and RhoG; inhibits PI3K/Akt and Rho/ROCK |
Tissues expressed | During early mouse development, EphA2 is expressed in rhombomere 4 of the hindbrain [310], in distal regions of limb bud mesenchyme and various fetal epithelia [311]. In the adult EphA2 is expressed at low levels in epithelial tissue; highly upregulated in malignant cellular phenotypes including metastases |
Human Diseases | EphA2 is associated with age-related cortical cataract |
Knockout Mouse phenotype | EphA2 null mice develop skin tumors with an increased frequency and shortened latency. Moreover, tumors in homozygous knockout mice grow faster and are twice as likely to show invasive malignant progression [239] |
Receptor at a glance: EphA3
Chromosome location | Human: chromosome 3: 89,156,674–89,531,284; forward strand Mouse: chromosome 16: 63,543,364–63,863,984; reverse stranda |
Gene size (bp) | Human: 374,611. Mouse: 320,621a |
Intron/exon numbers | 17 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—5,809; 5′ UTR—225; ORF—2,952; 3′ UTR—2,632 Mouse: mRNA—5,659; 5′ UTR—111; ORF—2,595; 3′ UTR—2,593a |
Amino acid number | Human: 983. Mouse: 984a |
kDa | Human: 110. Mouse: 110b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | EphrinA1, −A2, −A3, −A4, −A5 |
Known dimerizing partners | EphA3; EphB2 [325] |
Pathways regulated | Activates RhoA |
Tissues expressed | Expression is highest in the brain, also detected in testis. In the developing heart, EphA3 is expressed by mesenchymal cells of the endocardial cushions |
Human diseases | Defects in EphA3 may be a cause of colorectal cancer. It was also identified in a homozygous haplotype mapping screen for genes associated with autism spectrum disorders |
Knockout mouse phenotype | EphA3 mutants show defects in heart development, with hypoplasia of atrioventricular endocardial cushions. ~75 % of homozygous mutants die within 48 hours after birth due to cardiac dysfunction [152]. Survivors develop normally with no indications of cardiac abnormalities. In EphA3; EphA4 double knockouts, hypaxial motor nerves are misguided into the DRGs [100], and hypaxial sensory projections are disturbed [101] |
Receptor at a glance: EphA4
Chromosome location | Human: chromosome 2: 222,282,747–222,438,922; reverse strand Mouse: chromosome 1: 77,363,760–77,511,663; reverse stranda |
Gene size (bp) | Human: 156,176. Mouse: 147,904a |
Intron/exon numbers | 18 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—6,346; 5′ UTR—42; ORF—2,961; 3′ UTR—3,343 Mouse: mRNA—6,328; 5′ UTR—57; ORF—2,961; 3′ UTR—3,310a |
Amino acid number | Human: 986. Mouse: 986b |
kDa | Human: 110. Mouse: 110b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | ephrinA1, -A2, -A3, -A4, -A5, -B2, and -B3 |
Known dimerizing partners | EphA4 |
Pathways regulated | Activates RhoA; inhibits Rac1, Rap1, Rap2, and integrin pathway. EphA4 intracellular domain activates Rac1 |
Tissues expressed | Developing nervous system: hindbrain, several neuronal subpopulations in spinal cord, cortex, hippocampus, striatum, thalamus, and retina. Developing cardiovascular system: CNS endothelial cells; neural crest cells; embryonic stem cells of the inner cell mass. Adult brain: hippocampus, amygdala, adult stem cells in SVZ; spinal cord; thyroid: follicular epithelium; kidney; lung; skeletal muscle; thymus; blood vessels: smooth muscle; platelets; stem cells of hair bulge. Cancer tumors: colon carcinoma, prostate tumors, pancreatic ductal adenocarcinoma |
Human diseases | Differential expression of EphA4 is associated with metastatic melanoma, transition from prostatic intraepithelial neoplasia to invasive prostate cancer, and pancreatic ductal adenocarcinoma. Implicated as disease modifier in amyotrophic lateral sclerosis |
Knockout Mouse phenotype | Axon guidance: Loss of coordination of limb movement associated with disruptions of central pattern generators; corticospinal tract; thalamocortical mapping; anterior commissure; limb motor neuron projection; retinotectal projection. Proliferation of cortical progenitors: diminished cortical size. Aberrant spine morphology. Defective Schaffer-collateral LTP and LTD. Impaired amygdala LTP. Abnormal CNS vascular structure. Defective T-cell development |
Receptor at a glance: EphA5
Chromosome location | Human: chromosome 4: 66,185,281–66,536,213; reverse strand Mouse: chromosome 5: 84,486,816–84,846,407; reverse stranda |
Gene size (bp) | Human: 350,933. Mouse: 359,592a |
Intron/exon numbers | 18 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—8,266; 5′ UTR—601; ORF—3,114; 3′ UTR—4,551 Mouse: mRNA—4,298; 5′ UTR—416; ORF—2,631; 3′ UTR—1,251a |
Amino acid number | Human: 1,037. Mouse: 876b |
kDa | Human: 115. Mouse: 97b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | EphrinA1, −A2, −A3, −A4, −A5 |
Known dimerizing partners | EphA5 |
Pathways regulated | Activates Cdc42 |
Tissues expressed | Specifically expressed in the brain, with high levels in cortical neurons and cerebellar Purkinje cells. In addition, EphA5 is detected in the amygdala, medial septum, nucleus of the diagonal band, olfactory bulb, and retina. Outside the nervous system, EphA5 is expressed in pancreatic islet cells |
Human diseases | |
Knockout mouse phenotype | Homozygous mutant mice are overtly normal but show defects of retinotectal mapping, with temporal axons shifted posteriorly and nasal axons anteriorly [113]. EphA5 knockouts also have altered aggressive behavior [190] |
Receptor at a glance: EphA6
Chromosome location | Human: chromosome 3: 96,533,425–97,471,304; forward strand Mouse: chromosome 16: 59,653,309–60,605,357; reverse stranda |
Gene size (bp) | Human: 937,880. Mouse: 952,049a |
Intron/exon numbers | 18 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—3,971; 5′ UTR—38; ORF—3,393; 3′ UTR—540 Mouse: mRNA—3,643; ORF—3,108; 3′ UTR—535a |
Amino acid number | Human: 1035. Mouse: 1035b |
kDa | Human: 116. Mouse: 116b |
Posttranslational modifications | Tyrosine phosphorylationc, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | EphrinA1, −A2, −A3, −A4, −A5 |
Known dimerizing partners | EphA6 |
Pathways regulated | No signaling pathways known |
Tissues expressed | During mouse development EphA6 is expressed in the accessory olfactory bulb (AOB), the site of axonal projections from the vomeronasal organ sensory neurons [139], and in retinal ganglion cells [107]. In adult mice, EphA6 is expressed predominantly in neurons in various neuronal populations [345] |
Human diseases | |
Knockout Mouse phenotype | Behavioral deficits specifically in tests of learning and memory [189] |
Receptor at a glance: EphA7
Chromosome location | Human: chromosome 6: 93,949,738-94,129,265; reverse strand Mouse: chromosome 4: 28,740,281-28,894,649; forward stranda |
Gene size (bp) | Human: 179,507. Mouse: 154,369a |
Intron/exon numbers | 17 exonsa |
mRNA size (5′, ORF, 3′) | Human full-length isoform: mRNA—6,588; 5′ UTR—185, ORF—2,997; 3′ UTR—3406 Mouse full-length isoform: mRNA, 6,746; 5′ UTR—253; ORF—2,997; 3′ UTR—3,496a |
Amino acid number | Human: full-length isoform—998; truncated isoform—450 Mouse: full-length isoform—998; truncated isoforms—610 and 626b |
kDa | Human: full-length isoform—112; truncated isoform—51. Mouse: full-length isoform—112; truncated isoforms—68 and 70b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylationb |
Domains | Full-length isoform: N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif. The truncated transmembrane mouse isoforms lack the kinase domain as well as the SAM domain and PDZ-binding motif. The secreted human isoform lacks the FN2 and all following domains |
Ligands | EphrinA1, −A2, −A3, −A4, −A5 |
Known dimerizing partners | EphA7; EphA2 (shown for the secreted isoform of human EphA7) [287] |
Pathways regulated | Activates caspase 3-dependent apoptosis; activates ERK |
Tissues expressed | Widely expressed in the embryo. In adult, expression restricted to hippocampus, testis, and spleen. EphA7 truncated isoform is expressed in lymphoma and lung cancer |
Human Diseases | |
Knockout Mouse phenotype | Most of the mutants are viable and fertile and show no gross abnormalities. Retinotectal mapping defects were observed, with nasal axons forming ectopic termination zones in the anterior SC [120]. Cortical size is increased due to reduced apoptosis of progenitor cells, and 10 percent of the embryos display exencephalic overgrowth of forebrain tissues [52]. Some homozygous mutants display anencephaly, possibly due to defects of neural tube closure [41]. Mutants also exhibit increased proliferation of neural progenitor cells in the lateral ventricle wall of the adult brain [244] |
Receptor at a glance: EphA8
Chromosome location | Human: Chromosome 1: 22,890,057-22,930,087 forward strand Mouse: Chromosome 4: 136,485,334-136,512,731 reverse stranda |
Gene size (bp) | Human: 40,031. Mouse: 27,398a |
Intron/exon numbers | 17 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—4,943; 5′ UTR—72; ORF—3,018; 3′ UTR—1,853 Mouse: mRNA—4,713; 5′ UTR—69; ORF −3,015; 3′ UTR—1,629a |
Amino acid number | Human: 1,005. Mouse: 1,004b |
kDa | Human: 111. Mouse: 111b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylation, ubiquitinationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | EphrinA2, −A3, −A5 |
Known dimerizing partners | EphA8 |
Pathways regulated | Activates MAPK, Rac, p100γ PI3-kinase, and integrin pathways |
Tissues expressed | Specifically expressed in the central nervous system. First detected at E10.5 with high levels near the midline region of the tectum and to a lower extent in discrete regions of hindbrain, in the dorsal horn of the spinal cord, and in the naso-lacrimal groove. The expression decreases at E12.5 and is barely detectable at E17.5. Not detected at postnatal stages |
Human Diseases | |
Knockout Mouse phenotype | Mice are viable and fertile, and mostly normal, but exhibit a defect in midline guidance of commissural fibers connecting the superior colliculus with the contralateral inferior colliculus, which misproject into the ipsilateral spinal cord [77] |
Receptor at a glance: EphA10
Chromosome location | Human: chromosome 1: 38,179,552-38,230,805; reverse strand Mouse: chromosome 4: 124,558,143-124,595,044; forward stranda |
Gene size (bp) | Human: 51,254. Mouse: 36,902a |
Intron/exon numbers | 17 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—5,425; 5′ UTR—no information; ORF—3,027; 3′ UTR—2,398 Mouse: no informationa |
Amino acid number | Human: 1,008. Mouse: 1,007b |
kDa | Human: 110b. Mouse: 109b |
Posttranslational modifications | N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain (lacking in one isoform), PDZ-binding motif |
Ligands | EphrinA1, −A2, −A3, −A4, −A5 |
Known dimerizing partners | No information |
Pathways regulated | No information |
Tissues expressed | Testis |
Human Diseases | No information |
Knockout Mouse phenotype | No information |
Receptor at a glance: EphB1
Chromosome location | Human: chromosome 3: 134,514,104-134,979,309; forward strand Mouse: chromosome 9: 101,824,458-102,257,023; reverse stranda |
Gene size (bp) | Human: 465,206. Mouse: 432,566a |
Intron/exon numbers | 16 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—4,672; 5′UTR—370; ORF—2,955; 3′UTR—1,347 Mouse: mRNA—4,667; 5′UTR—354; ORF—2,955; 3′UTR—1358a |
Amino acid number | Human: 984. Mouse: 984b |
kDa | Human: 110 Mouse: 110b |
Posttranslational modifications | Phosphorylation, N-glycosylation, ubiquitinationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | EphrinB1, −B2, −B3 |
Known dimerizing partners | EphB1, EphB6 [373] |
Pathways regulated | MAPK/ERK, c-Jun, αvβ3 and α5β1 integrin |
Tissues expressed | Preferentially expressed in the brain |
Human diseases | Implemented in different cancers |
Knockout Mouse phenotype | Reduction of the ipsilateral retinotectal projection [130]. Reduced neural progenitors in the hippocampus [248]. EphB1; EphB2; EphB3-triple knockout display reduced spine density in the hippocampus [169] |
Receptor at a glance: EphB2
Chromosome location | Human: chromosome 1: 23,037,458-23,241,818; forward strand Mouse: chromosome 4: 136,203,454-136,391,903; reverse stranda |
Gene size (bp) | Human: 204,361. Mouse: 188,450a |
Intron/exon numbers | Human: 17 exons. Mouse: 16 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—4,641; 5′ UTR—18; ORF—3,168; 3′ UTR—1,455 Mouse: mRNA—4,804; 5′ UTR—126; ORF—2,964; 3′UTR—1,714a |
Amino acid number | Human: 1,055. Mouse: 994b |
kDa | Human: 117, Mouse: 111b |
Posttranslational modifications | Tyrosine phosphorylation, possibly serine/threonine phosphorylationc, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | ephrinB1, −B2, −B3, −A5, Reelin |
Known dimerizing partners | EphB2, EphA3[325] |
Pathways regulated | p110-PI3K, Rap1, RhoA, Rac1, Cdc42, Erk, ROCK-LIMK1-cofilin |
Tissues expressed | Endothelial cells in the vascular system, epithelium of intestinal colonic crypt, thymus. Nervous system: ventral midbrain, diencephalon, developing hindbrain, amygdala, cerebellum, subventricular zone walls, retinotectal system, motor neurons. Neural crest cells, inner ear epithelium, skeletal muscles |
Human Diseases | Colorectal cancer, breast cancer, Alzheimer’s Disease, anxiety |
Knockout Mouse phenotype | Defects in ventral midbrain development [405], axon guidance errors at the midline [71], defective development of corpus callosum, cleft palate [73], defects in synaptic functions in the hippocampus, LTP and LTD impairment [168], defective dendritic spine morphogenesis [169], vascular defects [144], defective inner ear morphogenesis and circling behavior [135], defects in the morphology of the pancreas, urorectal development [158], thymus development [406], disorganized cell sorting in the intestinal epithelium [26], plasticity of adult stem cells [250], increased proliferation of stem cells in the SVZ [245] |
Receptor at a glance: EphB3
Chromosome location | Human: chromosome 3: 184,279,572-184,300,197; forward strand Mouse: chromosome 16: 21,204,828-21,223,377; forward stranda |
Gene size (bp) | Human: 20,626. Mouse: 18,550a |
Intron/exon numbers | 16 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—4,236; 5′ UTR—452; ORF—2997; 3′ UTR—787 Mouse: mRNA—4,185; 5′ UTR—415; ORF—2,982; 3′ UTR—788a |
Amino acid number | Human: 998. Mouse: 993b |
kDa | Human: 110. Mouse: 110b |
Posttranslational modifications | Tyrosine phosphorylation, Serine/Threonine phosphorylationc, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | ephrinB1, −B2, −B3 |
Known dimerizing partners | EphB3, EphB2 |
Pathways regulated | ADAM-10-E-cadherin, RhoA, Rac1/Cdc42, AF-6-Ras GTPase/Disheveled-Daam1, Fyn/Src-Crk-rasGAP-Ras GTPase, p53-cell proliferation, Akt-cell survival, PICK1-PKC-α-D-serine synthesis |
Tissues expressed | Developing hindbrain and ventral midbrain [405], basal nuclei in the striatum, stem cells in the SVZ, retinal ganglion cells during development, Paneth cells and stem cells in the small and large intestine, pharynx, salivary glands, thymus, neural crest cells, inner ear efferent fibers, developing skeletal elements, secondary palate, pancreatic epithelium, macrophages, vestibular epithelium |
Human Diseases | Colorectal cancer, prostate cancer, ovarian cancer |
Knockout Mouse phenotype | Midline guidance errors [74], proliferation defects of the adult stem cells in the SVZ [247], vascular defects[144], skeletal abnormalities[27], cell migration in the intestinal epithelium, cleft palate [416], defective pancreatic branching [159], disturbed morphogenesis and regeneration of the intestinal epithelium [26, 228, 411], defective thymus development [406], affected development of the urogenital system [158] |
Receptor at a glance: EphB4
Chromosome location | Human: chromosome 7: 100,400,187-100,425,121; reverse strand Mouse: chromosome 5: 137,791,337-137,819,897; forward stranda |
Gene size (bp) | Human: 24,935. Mouse: 28,561a |
Intron/exon numbers | 17 exonsa |
mRNA size (5′, ORF, 3′) | Human: mRNA—4,329; 5′ UTR—469; ORF—2,964; 3′ UTR—896 Mouse: mRNA—4,340; 5′ UTR—489; ORF—2,964; 3′ UTR—887a |
Amino acid number | Human: 987. Mouse: 987b |
kDa | Human: 108. Mouse: 109b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | All ephrinBs, but ephrinB2 is preferred |
Known dimerizing partners | EphB4, EphB6 [258] |
Pathways regulated | PI3K/Akt, Abl/Crk, RhoA, Cdc42, Rac1 |
Tissues expressed | Placenta, kidney, liver, lung, breast, pancreas, skeletal and heart muscle, lymph vessels, venous epithelium. Low levels in fetal brain, not expressed in adult brain |
Human Diseases | Colorectal cancer, breast cancer |
Knockout Mouse phenotype | Defects in angiogenesis, leading to embryonic lethality [141] |
Receptor at a glance: EphB6
Chromosome location | Human: chromosome 7: 142,552,792-142,568,847; forward strand Mouse: chromosome 6: 41,555,481-41,570,508; forward stranda |
Gene size (bp) | Human: 16,056. Mouse: 15,028a |
Intron/exon numbers | Human: 20. Mouse: 18a |
mRNA size (5′, ORF, 3′) | Human: mRNA—4,043; 5′UTR—787; ORF—3,066; 3′UTR—190 Mouse: mRNA—3,762; 5′UTR—512; ORF—3,045; 3′UTR—205a |
Amino acid number | Human: 1,021. Mouse: 1,014b |
kDa | Human: 111. Mouse: 110b |
Posttranslational modifications | Tyrosine phosphorylation, N-glycosylationb |
Domains | N-terminal ligand-binding domain (LBD), cysteine-rich region, two fibronectin type III domains (FN1 and FN2), single transmembrane helix, juxtamembrane region, inactive tyrosine kinase domain, sterile-α motif (SAM) domain, PDZ-binding motif |
Ligands | ephrinB1, −B2 |
Known dimerizing partners | |
Pathways regulated | Activates c-Cbl/Abl pathway, inhibits JNK pathway |
Tissues expressed | Brain, noninvasive breast carcinoma cell lines, pancreas |
Human Diseases | Non-small cell lung cancer |
Knockout Mouse phenotype | Compromised T-cell function, including proliferation and secretion, and reduced severity of experimental autoimmune encephalitis (EAE) when stimulated by MOG33–55 [219] |
5.1.1 Notes
1. Ensembl (http://www.ensembl.org)
2. UniProt (http://www.uniprot.org)
3. Phosphosite (http://www.phosphosite.org)
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Gaitanos, T., Dudanova, I., Sakkou, M., Klein, R., Paixão, S. (2015). The Eph Receptor Family. In: Wheeler, D., Yarden, Y. (eds) Receptor Tyrosine Kinases: Family and Subfamilies. Springer, Cham. https://doi.org/10.1007/978-3-319-11888-8_5
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