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Eph-dependent cell-cell adhesion and segregation in development and cancer

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Abstract

Numerous studies attest to essential roles for Eph receptors and their ephrin ligands in controlling cell positioning and tissue patterning during normal and oncogenic development. These studies suggest multiple, sometimes contradictory, functions of Eph-ephrin signalling, which under different conditions can promote either spreading and cell-cell adhesion or cytoskeletal collapse, cell rounding, de-adhesion and cell-cell segregation. A principle determinant of the balance between these two opposing responses is the degree of receptor/ligand clustering and activation. This equilibrium is likely altered in cancers and modulated by somatic mutations of key Eph family members that have emerged as candidate cancer markers in recent profiling studies. In addition, cross-talk amongst Ephs and with other signalling pathways significantly modulates cell-cell adhesion, both between and within Eph- and ephrin-expressing cell populations. This review summarises our current understanding of how Eph receptors control cell adhesion and morphology, and presents examples demonstrating the importance of these events in normal development and cancer.

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Abbreviations

ADAM10:

A disintegrin and metalloprotease 10

ALL:

Acute lymphoblastic leukaemia

Cas:

Crk-associated substrate

CRC:

Colorectal cancer

Crk:

CT10 regulator of kinase

ECD:

Extracellular domain

ECM:

Extra-cellular matrix

EGFR:

Epithelial growth factor receptor

FAK:

Focal adhesion kinase

GAP:

GTPase activating protein

GEF:

Guanine nucleotide exchange factor

GPI:

Glycosyl phosphatidylinositol

JNK:

c-Jun N-terminal kinase

MMP:

Matrix metalloprotease

NMDA:

N-methyl d-aspartate

PBM:

PDZ-binding motif

PDZ:

Postsynaptic density protein/discs large/zona occludens protein (domain)

PH:

Pleckstrin homology (domain)

PI3K:

Phosphatidylinositol 3′-kinase

PLC:

Phospholipase C

PTB:

Phospho-tyrosine binding (domain)

PTP:

Protein tyrosine phosphatase

PY:

Phospho-tyrosine

ROCK:

Rho-associated coiled-coil-containing protein kinase

ROS:

Reactive oxygen species

RTK:

Receptor tyrosine kinase

SAM:

Sterile alpha motif

SH2:

Src homology 2 (domain)

TNFα:

Tumour necrosis factor α

References

  1. Himanen J-P, Saha N, Nikolov DB (2007) Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol 19:534–542

    Article  PubMed  CAS  Google Scholar 

  2. Lackmann M, Boyd AW (2008) Eph, a protein family coming of age: more confusion, insight, or complexity? Sci Signal 1: re2

  3. Pasquale EB (2008) Eph–ephrin bidirectional signaling in physiology and disease. Cell 133:38–52

    Article  PubMed  CAS  Google Scholar 

  4. Merlos-Suárez A, Batlle E (2008) Eph–ephrin signalling in adult tissues and cancer. Curr Opin Cell Biol 20:194–200

    Article  PubMed  CAS  Google Scholar 

  5. Genander M, Frisén J (2010) Ephrins and Eph receptors in stem cells and cancer. Curr Opin Cell Biol 22:611–616

    Article  PubMed  CAS  Google Scholar 

  6. Pasquale EB (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10:165–180

    Article  PubMed  CAS  Google Scholar 

  7. Janes PW, Adikari S, Lackmann M (2008) Eph/ephrin signalling and function in oncogenesis: lessons from embryonic development. Curr Cancer Drug Targets 8:473–479

    Article  PubMed  CAS  Google Scholar 

  8. Amit I, Wides R, Yarden Y (2007) Evolvable signaling networks of receptor tyrosine kinases: relevance of robustness to malignancy and to cancer therapy. Mol Syst Biol 3:151

    Article  PubMed  Google Scholar 

  9. Drescher U (2002) Eph family functions from an evolutionary perspective. Curr Opin Genet Dev 12:397–402

    Article  PubMed  CAS  Google Scholar 

  10. Suga H, Hoshiyama D, Kuraku S, Katoh K, Kubokawa K, Miyata T (1999) Protein tyrosine kinase cDNAs from amphioxus, hagfish, and lamprey: isoform duplications around the divergence of cyclostomes and gnathostomes. J Mol Evol 49:601–608

    Article  PubMed  CAS  Google Scholar 

  11. George SE, Simokat K, Hardin J, Chisholm AD (1998) The VAB-1 Eph receptor tyrosine kinase functions in neural and epithelial morphogenesis in C. elegans. Cell 92:633–643

    Article  PubMed  CAS  Google Scholar 

  12. Wang X, Roy PJ, Holland SJ, Zhang LW, Culotti JG, Pawson T (1999) Multiple ephrins control cell organization in C. elegans using kinase-dependent and -independent functions of the VAB-1 Eph receptor. Mol Cell 4:903–913

    Article  PubMed  CAS  Google Scholar 

  13. Eph Nomenclature Committee (1997) Unified nomenclature for Eph family receptors and their ligands, the ephrins. Cell 90:403–404

    Article  Google Scholar 

  14. Gale NW, Holland SJ, Valenzuela DM, Flenniken A, Pan L, Ryan TE, Henkemeyer M, Strebhardt K, Hirai H, Wilkinson DG, Pawson T, Davis S, Yancopoulos GD (1996) Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 17:9–19

    Article  PubMed  CAS  Google Scholar 

  15. Hirai H, Maru Y, Hagiwara K, Nishida J, Takaku F (1987) A novel putative tyrosine kinase receptor encoded by the eph gene. Science 238:1717–1720

    Article  PubMed  CAS  Google Scholar 

  16. Cooke JE, Kemp HA, Moens CB (2005) EphA4 is required for cell adhesion and rhombomere-boundary formation in the zebrafish. Curr Biol 15:536–542

    Article  PubMed  CAS  Google Scholar 

  17. Qin H, Noberini R, Huan X, Shi J, Pasquale EB, Song J (2009) Structural characterization of the EphA4-Ephrin-B2 complex reveals new features enabling Eph–ephrin binding promiscuity. J Biol Chem 285:644–654

    Article  PubMed  CAS  Google Scholar 

  18. Takemoto M, Fukuda T, Sonoda R, Murakami F, Tanaka H, Yamamoto N (2002) Ephrin–B3–EphA4 interactions regulate the growth of specific thalamocortical axon populations in vitro. Eur J Neurosci 16:1168–1172

    Article  PubMed  Google Scholar 

  19. Himanen JP, Chumley MJ, Lackmann M, Li C, Barton WA, Jeffrey PD, Vearing C, Geleick D, Feldheim DA, Boyd AW, Henkemeyer M, Nikolov DB (2004) Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7:501–509

    Article  PubMed  CAS  Google Scholar 

  20. Himanen JP, Rajashankar KR, Lackmann M, Cowan CA, Henkemeyer M, Nikolov DB (2001) Crystal structure of an Eph receptor–ephrin complex. Nature 414:933–938

    Article  PubMed  CAS  Google Scholar 

  21. Labrador JP, Brambilla R, Klein R (1997) The N-terminal globular domain of Eph receptors is sufficient for ligand binding and receptor signaling. EMBO J 16:3889–3897

    Article  PubMed  CAS  Google Scholar 

  22. Himanen JP, Yermekbayeva L, Janes PW, Walker JR, Xu K, Atapattu L, Rajashankar KR, Mensinga A, Lackmann M, Nikolov DB, Dhe-Paganon S (2010) Architecture of Eph receptor clusters. Proc Natl Acad Sci USA 107:10860–10865

    Article  PubMed  CAS  Google Scholar 

  23. Lackmann M, Oates AC, Dottori M, Smith FM, Do C, Power M, Kravets L, Boyd AW (1998) Distinct subdomains of the EphA3 receptor mediate ligand binding and receptor dimerization. J Biol Chem 273:20228–20237

    Article  PubMed  CAS  Google Scholar 

  24. Wimmer-Kleikamp SH, Janes PW, Squire A, Bastiaens PI, Lackmann M (2004) Recruitment of Eph receptors into signaling clusters does not require ephrin contact. J Cell Biol 164:661–666

    Article  PubMed  CAS  Google Scholar 

  25. Seiradake E, Harlos K, Sutton G, Aricescu AR, Jones EY (2010) An extracellular steric seeding mechanism for Eph–ephrin signaling platform assembly. Nat Struct Mol Biol 17:398–402

    Article  PubMed  CAS  Google Scholar 

  26. Himanen JP, Nikolov DB (2003) Eph signaling: a structural view. Trends Neurosci 26:46–51

    Article  PubMed  CAS  Google Scholar 

  27. Stapleton D, Balan I, Pawson T, Sicheri F (1999) The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization. Nat Struct Biol 6:44–49

    Article  PubMed  CAS  Google Scholar 

  28. Leone M, Cellitti J, Pellecchia M (2008) NMR studies of a heterotypic Sam-Sam domain association: the interaction between the lipid phosphatase Ship2 and the EphA2 receptor. Biochemistry 47:12721–12728

    Article  PubMed  CAS  Google Scholar 

  29. Zhuang G, Hunter S, Hwang Y, Chen J (2007) Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation. J Biol Chem 282:2683–2694

    Article  PubMed  CAS  Google Scholar 

  30. Davis S, Gale NW, Aldrich TH, Maisonpierre PC, Lhotak V, Pawson T, Goldfarb M, Yancopoulos GD (1994) Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266:816–819

    Article  PubMed  CAS  Google Scholar 

  31. Carter N, Nakamoto T, Hirai H, Hunter T (2002) EphrinA1-induced cytoskeletal re-organization requires FAK and p130(cas). Nat Cell Biol 4:565–573

    PubMed  CAS  Google Scholar 

  32. Dobrzanski P, Hunter K, Jones-Bolin S, Chang H, Robinson C, Pritchard S, Zhao H, Ruggeri B (2004) Antiangiogenic and antitumor efficacy of EphA2 receptor antagonist. Cancer Res 64:910–919

    Article  PubMed  CAS  Google Scholar 

  33. Lawrenson ID, Wimmer-Kleikamp SH, Lock P, Schoenwaelder SM, Down M, Boyd AW, Alewood PF, Lackmann M (2002) Ephrin-A5 induces rounding, blebbing and de-adhesion of EphA3- expressing 293T and melanoma cells by CrkII and Rho-mediated signalling. J Cell Sci 115:1059–1072

    PubMed  CAS  Google Scholar 

  34. Stein E, Lane AA, Cerretti DP, Schoecklmann HO, Schroff AD, Van Etten RL, Daniel TO (1998) Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev 12:667–678

    Article  PubMed  CAS  Google Scholar 

  35. Vearing C, Lee FT, Wimmer-Kleikamp S, Spirkoska V, To C, Stylianou C, Spanevello M, Brechbiel M, Boyd AW, Scott AM, Lackmann M (2005) Concurrent binding of anti-EphA3 antibody and ephrin-A5 amplifies EphA3 signaling and downstream responses: potential as EphA3-specific tumor-targeting reagents. Cancer Res 65:6745–6754

    Article  PubMed  CAS  Google Scholar 

  36. Vearing CJ, Lackmann M (2005) Eph receptor signalling; dimerisation just isn’t enough. Growth Factors 23:67–76

    Article  PubMed  CAS  Google Scholar 

  37. Tanaka M, Kamo T, Ota S, Sugimura H (2003) Association of dishevelled with Eph tyrosine kinase receptor and ephrin mediates cell repulsion. EMBO J 22:847–858

    Article  PubMed  CAS  Google Scholar 

  38. van der Geer P, Hunter T, Lindberg RA (1994) Receptor protein–tyrosine kinases and their signal transduction pathways. Annu Rev Cell Biol 10:251–337

    Article  PubMed  Google Scholar 

  39. Zisch AH, Stallcup WB, Chong LD, Dahlin-Huppe K, Voshol J, Schachner M, Pasquale EB (1997) Tyrosine phosphorylation of L1 family adhesion molecules: implication of the Eph kinase Cek5. J Neurosci Res 47:655–665

    Article  PubMed  CAS  Google Scholar 

  40. Noren NK, Yang NY, Silldorff M, Mutyala R, Pasquale EB (2009) Ephrin-independent regulation of cell substrate adhesion by the EphB4 receptor. Biochem J 422:433–442

    Article  PubMed  CAS  Google Scholar 

  41. Day B, To C, Himanen JP, Smith FM, Nikolov DB, Boyd AW, Lackmann M (2005) Three distinct molecular surfaces in ephrin-A5 are essential for a functional interaction with EphA3. J Biol Chem 280:26526–26532

    Article  PubMed  CAS  Google Scholar 

  42. Smith FM, Vearing C, Lackmann M, Treutlein H, Himanen J, Chen K, Saul A, Nikolov D, Boyd AW (2004) Dissecting the EphA3/Ephrin-A5 interactions using a novel functional mutagenesis screen. J Biol Chem 279:9522–9531

    Article  PubMed  CAS  Google Scholar 

  43. Chung I, Akita R, Vandlen R, Toomre D, Schlessinger J, Mellman I (2010) Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature 464:783–787

    Article  PubMed  CAS  Google Scholar 

  44. Finger C, Escher C, Schneider D (2009) The single transmembrane domains of human receptor tyrosine kinases encode self-interactions. Sci Signal 2: ra56

  45. Binns KL, Taylor PP, Sicheri F, Pawson T, Holland SJ (2000) Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors. Mol Cell Biol 20:4791–4805

    Article  PubMed  CAS  Google Scholar 

  46. Davis TL, Walker JR, Loppnau P, Butler-Cole C, Allali-Hassani A, Dhe-Paganon S (2008) Autoregulation by the juxtamembrane region of the human ephrin receptor tyrosine kinase A3 (EphA3). Structure 16:873–884

    Article  PubMed  CAS  Google Scholar 

  47. Wiesner S, Wybenga-Groot LE, Warner N, Lin H, Pawson T, Forman-Kay JD, Sicheri F (2006) A change in conformational dynamics underlies the activation of Eph receptor tyrosine kinases. EMBO J 25:4686–4696

    Article  PubMed  CAS  Google Scholar 

  48. Wybenga-Groot LE, Baskin B, Ong SH, Tong J, Pawson T, Sicheri F (2001) Structural basis for autoinhibition of the Ephb2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 106:745–757

    Article  PubMed  CAS  Google Scholar 

  49. Singla N, Erdjument-Bromage H, Himanen Juha P, Muir Tom W, Nikolov Dimitar B (2011) A semisynthetic Eph receptor tyrosine kinase provides insight into ligand- induced kinase activation. Chem Biol 18:361–371

    Article  PubMed  CAS  Google Scholar 

  50. Fang WB, Brantley-Sieders DM, Hwang Y, Ham AJ, Chen J (2008) Identification and functional analysis of phosphorylated tyrosine residues within EphA2 receptor tyrosine kinase. J Biol Chem 283:16017–16026

    Article  PubMed  CAS  Google Scholar 

  51. Warner N, Wybenga-Groot LE, Pawson T (2008) Analysis of EphA4 receptor tyrosine kinase substrate specificity using peptide-based arrays. FEBS J 275:2561–2573

    Article  PubMed  CAS  Google Scholar 

  52. Citri A, Yarden Y (2006) EGF–ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516

    Article  PubMed  CAS  Google Scholar 

  53. Freywald A, Sharfe N, Roifman CM (2002) The kinase-null EphB6 receptor undergoes transphosphorylation in a complex with EphB1. J Biol Chem 277:3823–3828

    Article  PubMed  CAS  Google Scholar 

  54. Truitt L, Freywald T, DeCoteau J, Sharfe N, Freywald A (2010) The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells. Cancer Res 70:1141–1153

    Article  PubMed  CAS  Google Scholar 

  55. Bush JO, Soriano P (2010) Ephrin-B1 forward signaling regulates craniofacial morphogenesis by controlling cell proliferation across Eph–ephrin boundaries. Genes Dev 24:2068–2080

    Article  PubMed  CAS  Google Scholar 

  56. Jorgensen C, Sherman A, Chen GI, Pasculescu A, Poliakov A, Hsiung M, Larsen B, Wilkinson DG, Linding R, Pawson T (2009) Cell-specific information processing in segregating populations of Eph receptor ephrin-expressing cells. Science 326:1502–1509

    Article  PubMed  CAS  Google Scholar 

  57. Janes PW, Griesshaber B, Atapattu L, Nievergall E, Hii L, Mensinga A, Chheang C, Day B, Boyd AW, Bastiaens PI, Jorgensen C, Pawson T, Lackmann M (2011) Eph receptor function is modulated by hetero-oligomerisation of A and B type Eph receptors. J Cell Biol. doi:10.1083/jcb.201104037

  58. Kholodenko BN, Hancock JF, Kolch W (2010) Signalling ballet in space and time. Nat Rev Mol Cell Biol 11:414–426

    Article  PubMed  CAS  Google Scholar 

  59. Fukai J, Yokote H, Yamanaka R, Arao T, Nishio K, Itakura T (2008) EphA4 promotes cell proliferation and migration through a novel EphA4-FGFR1 signaling pathway in the human glioma U251 cell line. Mol Cancer Ther 7:2768–2778

    Article  PubMed  CAS  Google Scholar 

  60. Yokote H, Fujita K, Jing X, Sawada T, Liang S, Yao L, Yan X, Zhang Y, Schlessinger J, Sakaguchi K (2005) Trans-activation of EphA4 and FGF receptors mediated by direct interactions between their cytoplasmic domains. Proc Natl Acad Sci USA 102:18866–18871

    Article  PubMed  CAS  Google Scholar 

  61. Park EK, Warner N, Bong YS, Stapleton D, Maeda R, Pawson T, Daar IO (2004) Ectopic EphA4 receptor induces posterior protrusions via FGF signaling in Xenopus embryos. Mol Biol Cell 15:1647–1655

    Article  PubMed  CAS  Google Scholar 

  62. Poliakov A, Cotrina ML, Pasini A, Wilkinson DG (2008) Regulation of EphB2 activation and cell repulsion by feedback control of the MAPK pathway. J Cell Biol 183:933–947

    Article  PubMed  CAS  Google Scholar 

  63. Larsen AB, Pedersen MW, Stockhausen MT, Grandal MV, van Deurs B, Poulsen HS (2007) Activation of the EGFR gene target EphA2 inhibits epidermal growth factor-induced cancer cell motility. Mol Cancer Res 5:283–293

    Article  PubMed  CAS  Google Scholar 

  64. Larsen AB, Stockhausen MT, Poulsen HS (2010) Cell adhesion and EGFR activation regulate EphA2 expression in cancer. Cell Signal 22:636–644

    Article  PubMed  CAS  Google Scholar 

  65. Komurov K, Padron D, Cheng T, Roth M, Rosenblatt KP, White MA (2010) Comprehensive mapping of the human kinome to epidermal growth factor receptor signaling. J Biol Chem 285:21134–21142

    Article  PubMed  CAS  Google Scholar 

  66. Deribe YL, Wild P, Chandrashaker A, Curak J, Schmidt MH, Kalaidzidis Y, Milutinovic N, Kratchmarova I, Buerkle L, Fetchko MJ, Schmidt P, Kittanakom S, Brown KR, Jurisica I, Blagoev B, Zerial M, Stagljar I, Dikic I (2009) Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. Sci Signal 2: ra84

  67. Thelemann A, Petti F, Griffin G, Iwata K, Hunt T, Settinari T, Fenyo D, Gibson N, Haley JD (2005) Phosphotyrosine signaling networks in epidermal growth factor receptor overexpressing squamous carcinoma cells. Mol Cell Proteomics 4:356–376

    Article  PubMed  CAS  Google Scholar 

  68. Brantley-Sieders DM, Zhuang G, Hicks D, Fang WB, Hwang Y, Cates JM, Coffman K, Jackson D, Bruckheimer E, Muraoka-Cook RS, Chen J (2008) The receptor tyrosine kinase EphA2 promotes mammary adenocarcinoma tumorigenesis and metastatic progression in mice by amplifying ErbB2 signaling. J Clin Invest 118:64–78

    Article  PubMed  CAS  Google Scholar 

  69. Kim I, Ryu YS, Kwak HJ, Ahn SY, Oh J-L, Yancopoulos GD, Gale NW, Koh GY (2002) EphB ligand, ephrinB2, suppresses the VEGF- and angiopoietin-1-induced Ras/mitogen-activated protein kinase pathway in venous endothelial cells. FASEB J 16(9):1126–1128

    Google Scholar 

  70. Ojima T, Takagi H, Suzuma K, Oh H, Suzuma I, Ohashi H, Watanabe D, Suganami E, Murakami T, Kurimoto M, Honda Y, Yoshimura N (2006) EphrinA1 inhibits vascular endothelial growth factor-induced intracellular signaling and suppresses retinal neovascularization and blood-retinal barrier breakdown. Am J Pathol 168:331–339

    Article  PubMed  CAS  Google Scholar 

  71. Halford MM, Armes J, Buchert M, Meskenaite V, Grail D, Hibbs ML, Wilks AF, Farlie PG, Newgreen DF, Hovens CM, Stacker SA (2000) Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nat Genet 25:414–418

    Article  PubMed  CAS  Google Scholar 

  72. Halford MM, Stacker SA (2001) Revelations of the RYK receptor. Bioessays 23:34–45

    Article  PubMed  CAS  Google Scholar 

  73. Trivier E, Ganesan TS (2002) RYK, a catalytically inactive receptor tyrosine kinase, associates with EphB2 and EphB3 but does not interact with AF-6. J Biol Chem 277:23037–23043

    Article  PubMed  CAS  Google Scholar 

  74. Kamitori K, Tanaka M, Okuno-Hirasawa T, Kohsaka S (2005) Receptor related to tyrosine kinase RYK regulates cell migration during cortical development. Biochem Biophys Res Commun 330:446–453

    Article  PubMed  CAS  Google Scholar 

  75. Salvucci O, de la Luz SM, Martina JA, McCormick PJ, Tosato G (2006) EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling. Blood 108:2914–2922

    Article  PubMed  CAS  Google Scholar 

  76. Sharfe N, Freywald A, Toro A, Dadi H, Roifman C (2002) Ephrin stimulation modulates T cell chemotaxis. Eur J Immunol 32:3745–3755

    Article  PubMed  CAS  Google Scholar 

  77. Duda DG, Kozin SV, Kirkpatrick ND, Xu L, Fukumura D, Jain RK (2011) CXCL12 (SDF1alpha)-CXCR4/CXCR7 pathway inhibition: an emerging sensitizer for anticancer therapies? Clin Cancer Res 17:2074–2080

    Article  PubMed  CAS  Google Scholar 

  78. Dalva MB, Takasu MA, Lin MZ, Shamah SM, Hu L, Gale NW, Greenberg ME (2000) EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103:945–956

    Article  PubMed  CAS  Google Scholar 

  79. Grunwald IC, Korte M, Wolfer D, Wilkinson GA, Unsicker K, Lipp HP, Bonhoeffer T, Klein R (2001) Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32:1027–1040

    Article  PubMed  CAS  Google Scholar 

  80. Henderson JT, Georgiou J, Jia Z, Robertson J, Elowe S, Roder JC, Pawson T (2001) The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32:1041–1056

    Article  PubMed  CAS  Google Scholar 

  81. Takasu MA, Dalva MB, Zigmond RE, Greenberg ME (2002) Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295:491–495

    Article  PubMed  CAS  Google Scholar 

  82. Kayser MS, McClelland AC, Hughes EG, Dalva MB (2006) Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors. J Neurosci 26:12152–12164

    Article  PubMed  CAS  Google Scholar 

  83. Pasquale EB (2005) Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 6:462–475

    Article  PubMed  CAS  Google Scholar 

  84. Jones TL, Chong LD, Kim J, Xu RH, Kung HF, Daar IO (1998) Loss of cell adhesion in Xenopus laevis embryos mediated by the cytoplasmic domain of XLerk, an erythropoietin-producing hepatocellular ligand. Proc Natl Acad Sci USA 95:576–581

    Article  PubMed  CAS  Google Scholar 

  85. Oates AC, Lackmann M, Power MA, Brennan C, Down LM, Do C, Evans B, Holder N, Boyd AW (1999) An early developmental role for eph–ephrin interaction during vertebrate gastrulation. Mech Dev 83:77–94

    Article  PubMed  CAS  Google Scholar 

  86. Winning RS, Scales JB, Sargent TD (1996) Disruption of cell adhesion in Xenopus embryos by Pagliaccio, an Eph- class receptor tyrosine kinase. Dev Biol 179:309–319

    Article  PubMed  CAS  Google Scholar 

  87. Brown A, Yates PA, Burrola P, Ortuno D, Vaidya A, Jessell TM, Pfaff SL, O’Leary DD, Lemke G (2000) Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102:77–88

    Article  PubMed  CAS  Google Scholar 

  88. Reber M, Burrola P, Lemke G (2004) A relative signalling model for the formation of a topographic neural map. Nature 431:847–853

    Article  PubMed  CAS  Google Scholar 

  89. Flanagan JG (2006) Neural map specification by gradients. Curr Opin Neurobiol 16:59–66

    Article  PubMed  CAS  Google Scholar 

  90. Lemke G, Reber M (2005) Retinotectal mapping: new insights from molecular genetics. Annu Rev Cell Dev Biol 21:551–580

    Article  PubMed  CAS  Google Scholar 

  91. McLaughlin T, O’Leary DD (2005) Molecular gradients and development of retinotopic maps. Annu Rev Neurosci 28:327–355

    Article  PubMed  CAS  Google Scholar 

  92. Mellitzer G, Xu Q, Wilkinson DG (1999) Eph receptors and ephrins restrict cell intermingling and communication. Nature 400:77–81

    Article  PubMed  CAS  Google Scholar 

  93. Xu Q, Mellitzer G, Robinson V, Wilkinson DG (1999) In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins. Nature 399:267–271

    Article  PubMed  CAS  Google Scholar 

  94. Nievergall E, Janes PW, Stegmayer C, Vail ME, Haj FG, Teng SW, Neel BG, Bastiaens PI, Lackmann M (2010) PTP1B regulates Eph receptor function and trafficking. J Cell Biol 191:1189–1203

    Article  PubMed  CAS  Google Scholar 

  95. Batlle E, Henderson JT, Beghtel H, van den Born MM, Sancho E, Huls G, Meeldijk J, Robertson J, van de Wetering M, Pawson T, Clevers H (2002) Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111:251–263

    Article  PubMed  CAS  Google Scholar 

  96. Bundesen LQ, Scheel TA, Bregman BS, Kromer LF (2003) Ephrin-B2 and EphB2 regulation of astrocyte-meningeal fibroblast interactions in response to spinal cord lesions in adult rats. J Neurosci 23:7789–7800

    PubMed  CAS  Google Scholar 

  97. Afshari FT, Kwok JC, Fawcett JW (2010) Astrocyte-produced ephrins inhibit schwann cell migration via VAV2 signaling. J Neurosci 30:4246–4255

    Article  PubMed  CAS  Google Scholar 

  98. Parrinello S, Napoli I, Ribeiro S, Digby PW, Fedorova M, Parkinson DB, Doddrell RD, Nakayama M, Adams RH, Lloyd AC (2010) EphB signaling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell 143:145–155

    Article  PubMed  CAS  Google Scholar 

  99. Davy A, Bush JO, Soriano P (2006) Inhibition of gap junction communication at ectopic Eph/ephrin boundaries underlies craniofrontonasal syndrome. PLoS Biol 4:e315

    Article  PubMed  CAS  Google Scholar 

  100. Barrios A, Poole RJ, Durbin L, Brennan C, Holder N, Wilson SW (2003) Eph/Ephrin signaling regulates the mesenchymal-to-epithelial transition of the paraxial mesoderm during somite morphogenesis. Curr Biol 13:1571–1582

    Article  PubMed  CAS  Google Scholar 

  101. Julich D, Geisler R, Holley SA (2005) Integrinalpha5 and delta/notch signaling have complementary spatiotemporal requirements during zebrafish somitogenesis. Dev Cell 8:575–586

    Article  PubMed  CAS  Google Scholar 

  102. Koshida S, Kishimoto Y, Ustumi H, Shimizu T, Furutani-Seiki M, Kondoh H, Takada S (2005) Integrinalpha5-dependent fibronectin accumulation for maintenance of somite boundaries in zebrafish embryos. Dev Cell 8:587–598

    Article  PubMed  CAS  Google Scholar 

  103. Stephen LJ, Fawkes AL, Verhoeve A, Lemke G, Brown A (2007) A critical role for the EphA3 receptor tyrosine kinase in heart development. Dev Biol 302:66–79

    Article  PubMed  CAS  Google Scholar 

  104. Frieden LA, Townsend TA, Vaught DB, Delaughter DM, Hwang Y, Barnett JV, Chen J (2010) Regulation of heart valve morphogenesis by Eph receptor ligand, ephrin-A1. Dev Dyn 239:3226–3234

    Article  PubMed  CAS  Google Scholar 

  105. O’Donnell M, Chance RK, Bashaw GJ (2009) Axon growth and guidance: receptor regulation and signal transduction. Annu Rev Neurosci 32:383–412

    Article  PubMed  CAS  Google Scholar 

  106. Frisen J, Yates PA, McLaughlin T, Friedman GC, O’Leary DD, Barbacid M (1998) Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20:235–243

    Article  PubMed  CAS  Google Scholar 

  107. Dottori M, Hartley L, Galea M, Paxinos G, Polizzotto M, Kilpatrick T, Bartlett PF, Murphy M, Kontgen F, Boyd AW (1998) EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci USA 95:13248–13253

    Article  PubMed  CAS  Google Scholar 

  108. Cheng HJ, Nakamoto M, Bergemann AD, Flanagan JG (1995) Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82:371–381

    Article  PubMed  CAS  Google Scholar 

  109. Drescher U, Kremoser C, Handwerker C, Loschinger J, Noda M, Bonhoeffer F (1995) In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 82:359–370

    Article  PubMed  CAS  Google Scholar 

  110. Feldheim DA, Vanderhaeghen P, Hansen MJ, Frisen J, Lu Q, Barbacid M, Flanagan JG (1998) Topographic guidance labels in a sensory projection to the forebrain. Neuron 21:1303–1313

    Article  PubMed  CAS  Google Scholar 

  111. Yates PA, Roskies AL, McLaughlin T, O’Leary DD (2001) Topographic-specific axon branching controlled by ephrin-As is the critical event in retinotectal map development. J Neurosci 21:8548–8563

    PubMed  CAS  Google Scholar 

  112. Kullander K, Mather NK, Diella F, Dottori M, Boyd AW, Klein R (2001) Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 29:73–84

    Article  PubMed  CAS  Google Scholar 

  113. Yokoyama N, Romero MI, Cowan CA, Galvan P, Helmbacher F, Charnay P, Parada LF, Henkemeyer M (2001) Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline. Neuron 29:85–97

    Article  PubMed  CAS  Google Scholar 

  114. Krull CE, Lansford R, Gale NW, Collazo A, Marcelle C, Yancopoulos GD, Fraser SE, Bronner-Fraser M (1997) Interactions of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration. Curr Biol 7:571–580

    Article  PubMed  CAS  Google Scholar 

  115. Smith A, Robinson V, Patel K, Wilkinson DG (1997) The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of branchial neural crest cells. Curr Biol 7:561–570

    Article  PubMed  CAS  Google Scholar 

  116. Wang HU, Anderson DJ (1997) Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18:383–396

    Article  PubMed  CAS  Google Scholar 

  117. Davy A, Aubin J, Soriano P (2004) Ephrin-B1 forward and reverse signaling are required during mouse development. Genes Dev 18:572–583

    Article  PubMed  CAS  Google Scholar 

  118. Bush JO, Soriano P (2009) Ephrin-B1 regulates axon guidance by reverse signaling through a PDZ-dependent mechanism. Genes Dev 23:1586–1599

    Article  PubMed  CAS  Google Scholar 

  119. Compagni A, Logan M, Klein R, Adams RH (2003) Control of skeletal patterning by ephrinB1-EphB interactions. Dev Cell 5:217–230

    Article  PubMed  CAS  Google Scholar 

  120. Gallarda BW, Bonanomi D, Muller D, Brown A, Alaynick WA, Andrews SE, Lemke G, Pfaff SL, Marquardt T (2008) Segregation of axial motor and sensory pathways via heterotypic trans-axonal signaling. Science 320:233–236

    Article  PubMed  CAS  Google Scholar 

  121. Klein R (2009) Bidirectional modulation of synaptic functions by Eph/ephrin signaling. Nat Neurosci 12:15–20

    Article  PubMed  CAS  Google Scholar 

  122. Lai KO, Ip NY (2009) Synapse development and plasticity: roles of ephrin/Eph receptor signaling. Curr Opin Neurobiol 19:275–283

    Article  PubMed  CAS  Google Scholar 

  123. Kayser MS, Nolt MJ, Dalva MB (2008) EphB receptors couple dendritic filopodia motility to synapse formation. Neuron 59:56–69

    Article  PubMed  CAS  Google Scholar 

  124. Torres R, Firestein BL, Dong H, Staudinger J, Olson EN, Huganir RL, Bredt DS, Gale NW, Yancopoulos GD (1998) PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21:1453–1463

    Article  PubMed  CAS  Google Scholar 

  125. Akaneya Y, Sohya K, Kitamura A, Kimura F, Washburn C, Zhou R, Ninan I, Tsumoto T, Ziff EB (2010) Ephrin-A5 and EphA5 interaction induces synaptogenesis during early hippocampal development. PLoS One 5:e12486

    Article  PubMed  CAS  Google Scholar 

  126. Ethell IM, Irie F, Kalo MS, Couchman JR, Pasquale EB, Yamaguchi Y (2001) Ephb/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31:1001–1013

    Article  PubMed  CAS  Google Scholar 

  127. Henkemeyer M, Itkis OS, Ngo M, Hickmott PW, Ethell IM (2003) Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol 163:1313–1326

    Article  PubMed  CAS  Google Scholar 

  128. Penzes P, Beeser A, Chernoff J, Schiller MR, Eipper BA, Mains RE, Huganir RL (2003) Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37:263–274

    Article  PubMed  CAS  Google Scholar 

  129. Segura I, Essmann CL, Weinges S, Acker-Palmer A (2007) Grb4 and GIT1 transduce ephrinB reverse signals modulating spine morphogenesis and synapse formation. Nat Neurosci 10:301–310

    Article  PubMed  CAS  Google Scholar 

  130. Fu WY, Chen Y, Sahin M, Zhao XS, Shi L, Bikoff JB, Lai KO, Yung WH, Fu AK, Greenberg ME, Ip NY (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67–76

    Article  PubMed  CAS  Google Scholar 

  131. Li W, Zheng Z, Keifer J (2011) Transsynaptic EphB/Ephrin-B signaling regulates growth of presynaptic boutons required for classical conditioning. J Neurosci 31:8441–8449

    Article  PubMed  CAS  Google Scholar 

  132. Adams RH, Eichmann A (2010) Axon guidancemolecules in vascular patterning. Cold Spring Harbor Perspect Biol 2:a001875

    Article  CAS  Google Scholar 

  133. Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13:295–306

    Article  PubMed  CAS  Google Scholar 

  134. Gerety SS, Anderson DJ (2002) Cardiovascular ephrinB2 function is essential for embryonic angiogenesis. Development 129:1397–1410

    PubMed  CAS  Google Scholar 

  135. Gerety SS, Wang HU, Chen ZF, Anderson DJ (1999) Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol Cell 4:403–414

    Article  PubMed  CAS  Google Scholar 

  136. Wang HU, Chen ZF, Anderson DJ (1998) Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93:741–753

    Article  PubMed  CAS  Google Scholar 

  137. Zhong TP, Childs S, Leu JP, Fishman MC (2001) Gridlock signalling pathway fashions the first embryonic artery. Nature 414:216–220

    Article  PubMed  CAS  Google Scholar 

  138. Pitulescu ME, Adams RH (2010) Eph/ephrin molecules—a hub for signaling and endocytosis. Genes Dev 24:2480–2492

    Article  PubMed  CAS  Google Scholar 

  139. Adams RH, Diella F, Hennig S, Helmbacher F, Deutsch U, Klein R (2001) The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 104:57–69

    Article  PubMed  CAS  Google Scholar 

  140. Foo SS, Turner CJ, Adams S, Compagni A, Aubyn D, Kogata N, Lindblom P, Shani M, Zicha D, Adams RH (2006) Ephrin-B2 controls cell motility and adhesion during blood-vessel-wall assembly. Cell 124:161–173

    Article  PubMed  CAS  Google Scholar 

  141. Herbert SP, Huisken J, Kim TN, Feldman ME, Houseman BT, Wang RA, Shokat KM, Stainier DY (2009) Arterial-venous segregation by selective cell sprouting: an alternative mode of blood vessel formation. Science 326:294–298

    Article  PubMed  CAS  Google Scholar 

  142. Cowan CA, Yokoyama N, Saxena A, Chumley MJ, Silvany RE, Baker LA, Srivastava D, Henkemeyer M (2004) Ephrin-B2 reverse signaling is required for axon pathfinding and cardiac valve formation but not early vascular development. Dev Biol 271:263–271

    Article  PubMed  CAS  Google Scholar 

  143. Brantley-Sieders DM, Caughron J, Hicks D, Pozzi A, Ruiz JC, Chen J (2004) EphA2 receptor tyrosine kinase regulates endothelial cell migration and vascular assembly through phosphoinositide 3-kinase-mediated Rac1 GTPase activation. J Cell Sci 117:2037–2049

    Article  PubMed  CAS  Google Scholar 

  144. Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL, Pasquale EB (2000) The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19:6043–6052

    Article  PubMed  CAS  Google Scholar 

  145. Sawamiphak S, Seidel S, Essmann CL, Wilkinson GA, Pitulescu ME, Acker T, Acker-Palmer A (2010) Ephrin-B2 regulates VEGFR2 function in developmental and tumour angiogenesis. Nature 465(7297):487–491

    Google Scholar 

  146. Wang Y, Nakayama M, Pitulescu ME, Schmidt TS, Bochenek ML, Sakakibara A, Adams S, Davy A, Deutsch U, Luthi U, Barberis A, Benjamin LE, Makinen T, Nobes CD, Adams RH (2010) Ephrin-B2 controls VEGF-induced angiogenesis and lymphangiogenesis. Nature 465(7297):483–486

    Google Scholar 

  147. Gale NW, Baluk P, Pan L, Kwan M, Holash J, DeChiara TM, McDonald DM, Yancopoulos GD (2001) Ephrin-B2 selectively marks arterial vessels and neovascularization sites in the adult, with expression in both endothelial and smooth- muscle cells. Dev Biol 230:151–160

    Article  PubMed  CAS  Google Scholar 

  148. Shin D, Garcia-Cardena G, Hayashi S, Gerety S, Asahara T, Stavrakis G, Isner J, Folkman J, Gimbrone MA Jr, Anderson DJ (2001) Expression of ephrinB2 identifies a stable genetic difference between arterial and venous vascular smooth muscle as well as endothelial cells, and marks subsets of microvessels at sites of adult neovascularization. Dev Biol 230:139–150

    Article  PubMed  CAS  Google Scholar 

  149. Salvucci O, Maric D, Economopoulou M, Sakakibara S, Merlin S, Follenzi A, Tosato G (2009) EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures. Blood 114:1707–1716

    Article  PubMed  CAS  Google Scholar 

  150. Kuijper S, Turner CJ, Adams RH (2007) Regulation of angiogenesis by Eph–ephrin interactions. Trends Cardiovasc Med 17:145–151

    Article  PubMed  CAS  Google Scholar 

  151. Helbling PM, Saulnier DM, Brandli AW (2000) The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development 127:269–278

    PubMed  CAS  Google Scholar 

  152. Pfaff D, Heroult M, Riedel M, Reiss Y, Kirmse R, Ludwig T, Korff T, Hecker M, Augustin HG (2008) Involvement of endothelial ephrin-B2 in adhesion and transmigration of EphB-receptor-expressing monocytes. J Cell Sci 121:3842–3850

    Article  PubMed  CAS  Google Scholar 

  153. Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476

    Article  PubMed  CAS  Google Scholar 

  154. Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19:397–410

    Article  PubMed  CAS  Google Scholar 

  155. Campbell TN, Robbins SM (2008) The Eph receptor/ephrin system: an emerging player in the invasion game. Curr Issues Mol Biol 10:61–66

    PubMed  CAS  Google Scholar 

  156. Chiari R, Hames G, Stroobant V, Texier C, Maillere B, Boon T, Coulie PG (2000) Identification of a tumor-specific shared antigen derived from an Eph receptor and presented to CD4 T cells on HLA class II molecules. Cancer Res 60:4855–4863

    PubMed  CAS  Google Scholar 

  157. Easty DJ, Bennett DC (2000) Protein tyrosine kinases in malignant melanoma. Melanoma Res 10:401–411

    Article  PubMed  CAS  Google Scholar 

  158. Hess AR, Margaryan NV, Seftor EA, Hendrix MJ (2007) Deciphering the signaling events that promote melanoma tumor cell vasculogenic mimicry and their link to embryonic vasculogenesis: role of the Eph receptors. Dev Dyn 236:3283–3296

    Article  PubMed  CAS  Google Scholar 

  159. Easty DJ, Herlyn M, Bennett DC (1995) Abnormal protein tyrosine kinase gene expression during melanoma progression and metastasis. Int J Cancer 60:129–136

    Article  PubMed  CAS  Google Scholar 

  160. Vecchi M, Confalonieri S, Nuciforo P, Vigano MA, Capra M, Bianchi M, Nicosia D, Bianchi F, Galimberti V, Viale G, Palermo G, Riccardi A, Campanini R, Daidone MG, Pierotti MA, Pece S, Di Fiore PP (2008) Breast cancer metastases are molecularly distinct from their primary tumors. Oncogene 27:2148–2158

    Article  PubMed  CAS  Google Scholar 

  161. Zelinski DP, Zantek ND, Stewart JC, Irizarry AR, Kinch MS (2001) EphA2 overexpression causes tumorigenesis of mammary epithelial cells. Cancer Res 61:2301–2306

    PubMed  CAS  Google Scholar 

  162. Fournier MV, Martin KJ, Kenny PA, Xhaja K, Bosch I, Yaswen P, Bissell MJ (2006) Gene expression signature in organized and growth-arrested mammary acini predicts good outcome in breast cancer. Cancer Res 66:7095–7102

    Article  PubMed  CAS  Google Scholar 

  163. Wu Q, Suo Z, Risberg B, Karlsson MG, Villman K, Nesland JM (2004) Expression of Ephb2 and Ephb4 in breast carcinoma. Pathol Oncol Res 10:26–33

    Article  PubMed  CAS  Google Scholar 

  164. Kumar SR, Singh J, Xia G, Krasnoperov V, Hassanieh L, Ley EJ, Scehnet J, Kumar NG, Hawes D, Press MF, Weaver FA, Gill PS (2006) Receptor tyrosine kinase EphB4 is a survival factor in breast cancer. Am J Pathol 169:279–293

    Article  PubMed  CAS  Google Scholar 

  165. Munarini N, Jager R, Abderhalden S, Zuercher G, Rohrbach V, Loercher S, Pfanner-Meyer B, Andres AC, Ziemiecki A (2002) Altered mammary epithelial development, pattern formation and involution in transgenic mice expressing the EphB4 receptor tyrosine kinase. J Cell Sci 115:25–37

    PubMed  CAS  Google Scholar 

  166. Brantley DM, Cheng N, Thompson EJ, Lin Q, Brekken RA, Thorpe PE, Muraoka RS, Cerretti DP, Pozzi A, Jackson D, Lin C, Chen J (2002) Soluble Eph A receptors inhibit tumor angiogenesis and progression in vivo. Oncogene 21:7011–7026

    Article  PubMed  CAS  Google Scholar 

  167. Ruiz JC, Robertson EJ (1994) The expression of the receptor-protein tyrosine kinase gene, eck, is highly restricted during early mouse development. Mech Dev 46:87–100

    Article  PubMed  CAS  Google Scholar 

  168. Chen J, Nachabah A, Scherer C, Ganju P, Reith A, Bronson R, Ruley HE (1996) Germ-line inactivation of the murine Eck receptor tyrosine kinase by gene trap retroviral insertion. Oncogene 12:979–988

    PubMed  CAS  Google Scholar 

  169. Cheng N, Brantley D, Fang WB, Liu H, Fanslow W, Cerretti DP, Bussell KN, Reith A, Jackson D, Chen J (2003) Inhibition of VEGF-dependent multistage carcinogenesis by soluble EphA receptors. Neoplasia 5:445–456

    PubMed  CAS  Google Scholar 

  170. Brantley-Sieders DM, Fang WB, Hicks DJ, Zhuang G, Shyr Y, Chen J (2005) Impaired tumor microenvironment in EphA2-deficient mice inhibits tumor angiogenesis and metastatic progression. FASEB J 19:1884–1886

    PubMed  CAS  Google Scholar 

  171. Brantley-Sieders DM, Fang WB, Hwang Y, Hicks D, Chen J (2006) Ephrin-A1 facilitates mammary tumor metastasis through an angiogenesis-dependent mechanism mediated by EphA receptor and vascular endothelial growth factor in mice. Cancer Res 66:10315–10324

    Article  PubMed  CAS  Google Scholar 

  172. Deroanne C, Vouret-Craviari V, Wang B, Pouyssegur J (2003) EphrinA1 inactivates integrin-mediated vascular smooth muscle cell spreading via the Rac/PAK pathway. J Cell Sci 116:1367–1376

    Article  PubMed  CAS  Google Scholar 

  173. Hayashi S, Asahara T, Masuda H, Isner JM, Losordo DW (2005) Functional ephrin-B2 expression for promotive interaction between arterial and venous vessels in postnatal neovascularization. Circulation 111:2210–2218

    Article  PubMed  CAS  Google Scholar 

  174. Foubert P, Silvestre JS, Souttou B, Barateau V, Martin C, Ebrahimian TG, Lere-Dean C, Contreres JO, Sulpice E, Levy BI, Plouet J, Tobelem G, Le Ricousse-Roussanne S (2007) PSGL-1-mediated activation of EphB4 increases the proangiogenic potential of endothelial progenitor cells. J Clin Invest 117:1527–1537

    Article  PubMed  CAS  Google Scholar 

  175. Mansson-Broberg A, Siddiqui AJ, Genander M, Grinnemo KH, Hao X, Andersson AB, Wardell E, Sylven C, Corbascio M (2008) Modulation of ephrinB2 leads to increased angiogenesis in ischemic myocardium and endothelial cell proliferation. Biochem Biophys Res Commun 373:355–359

    Article  PubMed  CAS  Google Scholar 

  176. Noren NK, Foos G, Hauser CA, Pasquale EB (2006) The EphB4 receptor suppresses breast cancer cell tumorigenicity through an Abl–Crk pathway. Nat Cell Biol 8:815–825

    Article  PubMed  CAS  Google Scholar 

  177. Erber R, Eichelsbacher U, Powajbo V, Korn T, Djonov V, Lin J, Hammes HP, Grobholz R, Ullrich A, Vajkoczy P (2006) EphB4 controls blood vascular morphogenesis during postnatal angiogenesis. EMBO J 25:628–641

    Article  PubMed  CAS  Google Scholar 

  178. Masood R, Xia G, Smith DL, Scalia P, Still JG, Tulpule A, Gill PS (2005) Ephrin B2 expression in Kaposi sarcoma is induced by human herpesvirus type 8: phenotype switch from venous to arterial endothelium. Blood 105:1310–1318

    Article  PubMed  CAS  Google Scholar 

  179. Hainaud P, Contreres JO, Villemain A, Liu LX, Plouet J, Tobelem G, Dupuy E (2006) The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res 66:8501–8510

    Article  PubMed  CAS  Google Scholar 

  180. Scehnet JS, Ley EJ, Krasnoperov V, Liu R, Manchanda PK, Sjoberg E, Kostecke AP, Gupta S, Kumar SR, Gill PS (2009) The role of Ephs, Ephrins, and growth factors in Kaposi sarcoma and implications of EphrinB2 blockade. Blood 113:254–263

    Article  PubMed  CAS  Google Scholar 

  181. Guo H, Miao H, Gerber L, Singh J, Denning MF, Gilliam AC, Wang B (2006) Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res 66:7050–7058

    Article  PubMed  CAS  Google Scholar 

  182. Batlle E, Bacani J, Begthel H, Jonkheer S, Gregorieff A, van de Born M, Malats N, Sancho E, Boon E, Pawson T, Gallinger S, Pals S, Clevers H (2005) EphB receptor activity suppresses colorectal cancer progression. Nature 435:1126–1130

    Article  PubMed  CAS  Google Scholar 

  183. Dopeso H, Mateo-Lozano S, Mazzolini R, Rodrigues P, Lagares-Tena L, Ceron J, Romero J, Esteves M, Landolfi S, Hernandez-Losa J, Castano J, Wilson AJ, Ramon y Cajal S, Mariadason JM, Schwartz S Jr, Arango D (2009) The receptor tyrosine kinase EPHB4 has tumor suppressor activities in intestinal tumorigenesis. Cancer Res 69:7430–7438

    Article  PubMed  CAS  Google Scholar 

  184. Xia G, Kumar SR, Masood R, Zhu S, Reddy R, Krasnoperov V, Quinn DI, Henshall SM, Sutherland RL, Pinski JK, Daneshmand S, Buscarini M, Stein JP, Zhong C, Broek D, Roy-Burman P, Gill PS (2005) EphB4 expression and biological significance in prostate cancer. Cancer Res 65:4623–4632

    Article  PubMed  CAS  Google Scholar 

  185. Stephenson SA, Slomka S, Douglas EL, Hewett PJ, Hardingham JE (2001) Receptor protein tyrosine kinase EphB4 is up-regulated in colon cancer. BMC Mol Biol 2:15

    Article  PubMed  CAS  Google Scholar 

  186. Takai N, Miyazaki T, Fujisawa K, Nasu K, Miyakawa I (2001) Expression of receptor tyrosine kinase EphB4 and its ligand ephrin-B2 is associated with malignant potential in endometrial cancer. Oncol Rep 8:567–573

    PubMed  CAS  Google Scholar 

  187. Berclaz G, Flutsch B, Altermatt HJ, Rohrbach V, Djonov V, Ziemiecki A, Dreher E, Andres AC (2002) Loss of EphB4 receptor tyrosine kinase protein expression during carcinogenesis of the human breast. Oncol Rep 9:985–989

    PubMed  CAS  Google Scholar 

  188. Guan M, Xu C, Zhang F, Ye C (2009) Aberrant methylation of EphA7 in human prostate cancer and its relation to clinicopathologic features. Int J Cancer 124:88–94

    Article  PubMed  CAS  Google Scholar 

  189. Wang J, Kataoka H, Suzuki M, Sato N, Nakamura R, Tao H, Maruyama K, Isogaki J, Kanaoka S, Ihara M, Tanaka M, Kanamori M, Nakamura T, Shinmura K, Sugimura H (2005) Downregulation of EphA7 by hypermethylation in colorectal cancer. Oncogene 24:5637–5647

    Article  PubMed  CAS  Google Scholar 

  190. Fox BP, Kandpal RP (2004) Invasiveness of breast carcinoma cells and transcript profile: Eph receptors and ephrin ligands as molecular markers of potential diagnostic and prognostic application. Biochem Biophys Res Commun 318:882–892

    Article  PubMed  CAS  Google Scholar 

  191. Nosho K, Yamamoto H, Takahashi T, Mikami M, Taniguchi H, Miyamoto N, Adachi Y, Arimura Y, Itoh F, Imai K, Shinomura Y (2007) Genetic and epigenetic profiling in early colorectal tumors and prediction of invasive potential in pT1 (early invasive) colorectal cancers. Carcinogenesis 28:1364–1370

    Article  PubMed  CAS  Google Scholar 

  192. Dottori M, Down M, Huttmann A, Fitzpatrick DR, Boyd AW (1999) Cloning and characterization of EphA3 (Hek) gene promoter: DNA methylation regulates expression in hematopoietic tumor cells. Blood 94:2477–2486

    PubMed  CAS  Google Scholar 

  193. Kuang SQ, Bai H, Fang ZH, Lopez G, Yang H, Tong W, Wang ZZ, Garcia-Manero G (2010) Aberrant DNA methylation and epigenetic inactivation of Eph receptor tyrosine kinases and ephrin ligands in acute lymphoblastic leukemia. Blood 115:2412–2419

    Article  PubMed  CAS  Google Scholar 

  194. Dong Y, Wang J, Sheng Z, Li G, Ma H, Wang X, Zhang R, Lu G, Hu Q, Sugimura H, Zhou X (2009) Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis. Mod Pathol 22:151–160

    Article  PubMed  CAS  Google Scholar 

  195. Herath NI, Doecke J, Spanevello MD, Leggett BA, Boyd AW (2009) Epigenetic silencing of EphA1 expression in colorectal cancer is correlated with poor survival. Br J Cancer 100:1095–1102

    Article  PubMed  CAS  Google Scholar 

  196. Clevers H, Batlle E (2006) EphB/EphrinB receptors and Wnt signaling in colorectal cancer. Cancer Res 66:2–5

    Article  PubMed  CAS  Google Scholar 

  197. Cortina C, Palomo-Ponce S, Iglesias M, Fernandez-Masip JL, Vivancos A, Whissell G, Huma M, Peiro N, Gallego L, Jonkheer S, Davy A, Lloreta J, Sancho E, Batlle E (2007) EphB–ephrin-B interactions suppress colorectal cancer progression by compartmentalizing tumor cells. Nat Genet 39:1376–1383

    Article  PubMed  CAS  Google Scholar 

  198. Genander M, Halford MM, Xu NJ, Eriksson M, Yu Z, Qiu Z, Martling A, Greicius G, Thakar S, Catchpole T, Chumley MJ, Zdunek S, Wang C, Holm T, Goff SP, Pettersson S, Pestell RG, Henkemeyer M, Frisen J (2009) Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell 139:679–692

    Article  PubMed  CAS  Google Scholar 

  199. Merlos-Suarez A, Barriga FM, Jung P, Iglesias M, Cespedes MV, Rossell D, Sevillano M, Hernando-Momblona X, da Silva-Diz V, Munoz P, Clevers H, Sancho E, Mangues R, Batlle E (2011) The Intestinal Stem Cell Signature Identifies Colorectal Cancer Stem Cells and Predicts Disease Relapse. Cell Stem Cell 8(5):511–524

    Google Scholar 

  200. Oricchio E, Nanjangud G, Wolfe AL, Schatz JH, Mavrakis KJ, Jiang M, Liu X, Bruno J, Heguy A, Olshen AB, Socci ND, Teruya-Feldstein J, Weis-Garcia F, Tam W, Shaknovich R, Melnick A, Himanen JP, Chaganti RS, Wendel HG (2011) The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma. Cell 147:554–564

    Article  PubMed  CAS  Google Scholar 

  201. Zantek ND, Azimi M, Fedor-Chaiken M, Wang B, Brackenbury R, Kinch MS (1999) E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell Growth Differ 10:629–638

    PubMed  CAS  Google Scholar 

  202. Noren NK, Pasquale EB (2007) Paradoxes of the EphB4 receptor in cancer. Cancer Res 67:3994–3997

    Article  PubMed  CAS  Google Scholar 

  203. Li X, Wang L, Gu JW, Li B, Liu WP, Wang YG, Zhang X, Zhen HN, Fei Z (2010) Up-regulation of EphA2 and down-regulation of EphrinA1 are associated with the aggressive phenotype and poor prognosis of malignant glioma. Tumour Biol 31:477–488

    Article  PubMed  CAS  Google Scholar 

  204. Noren NK, Lu M, Freeman AL, Koolpe M, Pasquale EB (2004) Interplay between EphB4 on tumor cells and vascular ephrin-B2 regulates tumor growth. Proc Natl Acad Sci USA 101:5583–5588

    Article  PubMed  CAS  Google Scholar 

  205. Alazzouzi H, Davalos V, Kokko A, Domingo E, Woerner SM, Wilson AJ, Konrad L, Laiho P, Espin E, Armengol M, Imai K, Yamamoto H, Mariadason JM, Gebert JF, Aaltonen LA, Schwartz S Jr, Arango D (2005) Mechanisms of inactivation of the receptor tyrosine kinase EPHB2 in colorectal tumors. Cancer Res 65:10170–10173

    Article  PubMed  CAS  Google Scholar 

  206. Davalos V, Dopeso H, Velho S, Ferreira AM, Cirnes L, Diaz-Chico N, Bilbao C, Ramirez R, Rodriguez G, Falcon O, Leon L, Niessen RC, Keller G, Dallenbach-Hellweg G, Espin E, Armengol M, Plaja A, Perucho M, Imai K, Yamamoto H, Gebert JF, Diaz-Chico JC, Hofstra RM, Woerner SM, Seruca R, Schwartz S Jr, Arango D (2006) High EPHB2 mutation rate in gastric but not endometrial tumors with microsatellite instability. Oncogene 26:308–311

    Article  PubMed  CAS  Google Scholar 

  207. Kan Z, Jaiswal BS, Stinson J, Janakiraman V, Bhatt D, Stern HM, Yue P, Haverty PM, Bourgon R, Zheng J, Moorhead M, Chaudhuri S, Tomsho LP, Peters BA, Pujara K, Cordes S, Davis DP, Carlton VE, Yuan W, Li L, Wang W, Eigenbrot C, Kaminker JS, Eberhard DA, Waring P, Schuster SC, Modrusan Z, Zhang Z, Stokoe D, de Sauvage FJ, Faham M, Seshagiri S (2010) Diverse somatic mutation patterns and pathway alterations in human cancers. Nature 466:869–873

    Article  PubMed  CAS  Google Scholar 

  208. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, Mandelker D, Leary RJ, Ptak J, Silliman N, Szabo S, Buckhaults P, Farrell C, Meeh P, Markowitz SD, Willis J, Dawson D, Willson JK, Gazdar AF, Hartigan J, Wu L, Liu C, Parmigiani G, Park BH, Bachman KE, Papadopoulos N, Vogelstein B, Kinzler KW, Velculescu VE (2006) The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274

    Article  PubMed  CAS  Google Scholar 

  209. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba II, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK (2008) Somatic mutations affect key pathways in lung adenocarcinoma. Nature 455:1069–1075

    Article  PubMed  CAS  Google Scholar 

  210. Balakrishnan A, Bleeker FE, Lamba S, Rodolfo M, Daniotti M, Scarpa A, van Tilborg AA, Leenstra S, Zanon C, Bardelli A (2007) Novel somatic and germline mutations in cancer candidate genes in glioblastoma, melanoma, and pancreatic carcinoma. Cancer Res 67:3545–3550

    Article  PubMed  CAS  Google Scholar 

  211. Corbo V, Ritelli R, Barbi S, Funel N, Campani D, Bardelli A, Scarpa A (2010) Mutational profiling of kinases in human tumours of pancreatic origin identifies candidate cancer genes in ductal and ampulla of vater carcinomas. PLoS One 5:e12653

    Article  PubMed  CAS  Google Scholar 

  212. Bonifaci N, Gorski B, Masojc B, Wokolorczyk D, Jakubowska A, Debniak T, Berenguer A, Serra Musach J, Brunet J, Dopazo J, Narod SA, Lubinski J, Lazaro C, Cybulski C, Pujana MA (2010) Exploring the link between germline and somatic genetic alterations in breast carcinogenesis. PLoS One 5:e14078

    Article  PubMed  CAS  Google Scholar 

  213. Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, Teague J, Butler A, Edkins S, Stevens C, Parker A, O’Meara S, Avis T, Barthorpe S, Brackenbury L, Buck G, Clements J, Cole J, Dicks E, Edwards K, Forbes S, Gorton M, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jones D, Kosmidou V, Laman R, Lugg R, Menzies A, Perry J, Petty R, Raine K, Shepherd R, Small A, Solomon H, Stephens Y, Tofts C, Varian J, Webb A, West S, Widaa S, Yates A, Brasseur F, Cooper CS, Flanagan AM, Green A, Knowles M, Leung SY, Looijenga LH, Malkowicz B, Pierotti MA, Teh BT, Yuen ST, Lakhani SR, Easton DF, Weber BL, Goldstraw P, Nicholson AG, Wooster R, Stratton MR, Futreal PA (2005) Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res 65:7591–7595

    PubMed  CAS  Google Scholar 

  214. Bardelli A, Parsons DW, Silliman N, Ptak J, Szabo S, Saha S, Markowitz S, Willson JK, Parmigiani G, Kinzler KW, Vogelstein B, Velculescu VE (2003) Mutational analysis of the tyrosine kinome in colorectal cancers. Science 300:949

    Article  PubMed  CAS  Google Scholar 

  215. Lin J, Gan CM, Zhang X, Jones S, Sjoblom T, Wood LD, Parsons DW, Papadopoulos N, Kinzler KW, Vogelstein B, Parmigiani G, Velculescu VE (2007) A multidimensional analysis of genes mutated in breast and colorectal cancers. Genome Res 17:1304–1318

    Article  PubMed  CAS  Google Scholar 

  216. Gylfe AE, Sirkia J, Ahlsten M, Jarvinen H, Mecklin JP, Karhu A, Aaltonen LA (2010) Somatic mutations and germline sequence variants in patients with familial colorectal cancer. Int J Cancer 127:2974–2980

    Article  PubMed  CAS  Google Scholar 

  217. Zogopoulos G, Jorgensen C, Bacani J, Montpetit A, Lepage P, Ferretti V, Chad L, Selvarajah S, Zanke B, Hudson TJ, Pawson T, Gallinger S (2008) Germline EPHB2 receptor variants in familial colorectal cancer. PLoS One 3:e2885

    Article  PubMed  CAS  Google Scholar 

  218. Huusko P, Ponciano-Jackson D, Wolf M, Kiefer JA, Azorsa DO, Tuzmen S, Weaver D, Robbins C, Moses T, Allinen M, Hautaniemi S, Chen Y, Elkahloun A, Basik M, Bova GS, Bubendorf L, Lugli A, Sauter G, Schleutker J, Ozcelik H, Elowe S, Pawson T, Trent JM, Carpten JD, Kallioniemi OP, Mousses S (2004) Nonsense-mediated decay microarray analysis identifies mutations of EPHB2 in human prostate cancer. Nat Genet 36:979–983

    Article  PubMed  CAS  Google Scholar 

  219. Ruhe JE, Streit S, Hart S, Wong CH, Specht K, Knyazev P, Knyazeva T, Tay LS, Loo HL, Foo P, Wong W, Pok S, Lim SJ, Ong H, Luo M, Ho HK, Peng K, Lee TC, Bezler M, Mann C, Gaertner S, Hoefler H, Iacobelli S, Peter S, Tay A, Brenner S, Venkatesh B, Ullrich A (2007) Genetic alterations in the tyrosine kinase transcriptome of human cancer cell lines. Cancer Res 67:11368–11376

    Article  PubMed  CAS  Google Scholar 

  220. Wimmer-Kleikamp SH, Lackmann M (2005) Eph-modulated cell morphology, adhesion and motility in carcinogenesis. IUBMB Life 57:421–431

    Article  PubMed  CAS  Google Scholar 

  221. Holmberg J, Clarke DL, Frisen J (2000) Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408:203–206

    Article  PubMed  CAS  Google Scholar 

  222. Dravis C, Yokoyama N, Chumley MJ, Cowan CA, Silvany RE, Shay J, Baker LA, Henkemeyer M (2004) Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol 271:272–290

    Article  PubMed  CAS  Google Scholar 

  223. Birgbauer E, Cowan CA, Sretavan DW, Henkemeyer M (2000) Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. Development 127:1231–1241

    PubMed  CAS  Google Scholar 

  224. Gu C, Park S (2001) The EphA8 receptor regulates integrin activity through p110gamma phosphatidylinositol-3 kinase in a tyrosine kinase activity-independent manner. Mol Cell Biol 21:4579–4597

    Article  PubMed  CAS  Google Scholar 

  225. Huynh-Do U, Stein E, Lane AA, Liu H, Cerretti DP, Daniel TO (1999) Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins. EMBO J 18:2165–2173

    Article  PubMed  CAS  Google Scholar 

  226. Hansen MJ, Dallal GE, Flanagan JG (2004) Retinal axon response to ephrin-as shows a graded, concentration-dependent transition from growth promotion to inhibition. Neuron 42:717–730

    Article  PubMed  CAS  Google Scholar 

  227. Matsuoka H, Obama H, Kelly ML, Matsui T, Nakamoto M (2005) Biphasic functions of the kinase-defective EphB6 receptor in cell adhesion and migration. J Biol Chem 280:29355–29363

    Article  PubMed  CAS  Google Scholar 

  228. von Philipsborn AC, Lang S, Loeschinger J, Bernard A, David C, Lehnert D, Bonhoeffer F, Bastmeyer M (2006) Growth cone navigation in substrate-bound ephrin gradients. Development 133:2487–2495

    Article  CAS  Google Scholar 

  229. Holmberg J, Frisen J (2002) Ephrins are not only unattractive. Trends Neurosci 25:239–243

    Article  PubMed  CAS  Google Scholar 

  230. Wimmer-Kleikamp SH, Nievergall E, Gegenbauer K, Adikari S, Mansour M, Yeadon T, Boyd AW, Patani NR, Lackmann M (2008) Elevated protein tyrosine phosphatase activity provokes Eph/ephrin-facilitated adhesion of pre-B leukemia cells. Blood 112:721–732

    Article  PubMed  CAS  Google Scholar 

  231. Shintani T, Ihara M, Sakuta H, Takahashi H, Watakabe I, Noda M (2006) Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O. Nat Neurosci 9:761–769

    Article  PubMed  CAS  Google Scholar 

  232. Astin JW, Batson J, Kadir S, Charlet J, Persad RA, Gillatt D, Oxley JD, Nobes CD (2010) Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells. Nat Cell Biol 12:1194–1204

    Article  PubMed  CAS  Google Scholar 

  233. Reiss K, Saftig P (2009) The “a disintegrin and metalloprotease” (ADAM) family of sheddases: Physiological and cellular functions. Semin Cell Dev Biol 20:126–137

    Article  PubMed  CAS  Google Scholar 

  234. Hattori M, Osterfield M, Flanagan JG (2000) Regulated cleavage of a contact-mediated axon repellent. Science 289:1360–1365

    Article  PubMed  CAS  Google Scholar 

  235. Janes PW, Saha N, Barton WA, Kolev MV, Wimmer-Kleikamp SH, Nievergall E, Blobel CP, Himanen JP, Lackmann M, Nikolov DB (2005) Adam meets Eph: an ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 123:291–304

    Article  PubMed  CAS  Google Scholar 

  236. Salaita K, Nair PM, Petit RS, Neve RM, Das D, Gray JW, Groves JT (2010) Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science 327:1380–1385

    Article  PubMed  CAS  Google Scholar 

  237. Janes PW, Wimmer-Kleikamp SH, Frangakis AS, Treble K, Griesshaber B, Sabet O, Grabenbauer M, Ting AY, Saftig P, Bastiaens PI, Lackmann M (2009) Cytoplasmic relaxation of active Eph controls ephrin shedding by ADAM10. PLoS Biol 7:e1000215

    Article  PubMed  CAS  Google Scholar 

  238. Reddy P, Slack JL, Davis R, Cerretti DP, Kozlosky CJ, Blanton RA, Shows D, Peschon JJ, Black RA (2000) Functional analysis of the domain structure of tumor necrosis factor-alpha converting enzyme. J Biol Chem 275:14608–14614

    Article  PubMed  CAS  Google Scholar 

  239. Blobel CP (2005) ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol 6:32–43

    Article  PubMed  CAS  Google Scholar 

  240. Litterst C, Georgakopoulos A, Shioi J, Ghersi E, Wisniewski T, Wang R, Ludwig A, Robakis NK (2007) Ligand binding and calcium influx induce distinct ectodomain/gamma-secretase-processing pathways of EphB2 receptor. J Biol Chem 282:16155–16163

    Article  PubMed  CAS  Google Scholar 

  241. Kopan R, Ilagan MXG (2004) [gamma]-Secretase: proteasome of the membrane? Nat Rev Mol Cell Biol 5:499–504

    Article  PubMed  CAS  Google Scholar 

  242. Wei S, Xu G, Bridges LC, Williams P, White JM, DeSimone DW (2010) ADAM13 induces cranial neural crest by cleaving class B ephrins and regulating Wnt signaling. Dev Cell 19:345–352

    Article  PubMed  CAS  Google Scholar 

  243. Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G, Robakis NK (2006) Metalloproteinase/presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J 25:1242–1252

    Article  PubMed  CAS  Google Scholar 

  244. Tomita T, Tanaka S, Morohashi Y, Iwatsubo T (2006) Presenilin-dependent intramembrane cleavage of ephrin-B1. Mol Neurodegener 1:2

    Article  PubMed  CAS  Google Scholar 

  245. Inoue E, Deguchi-Tawarada M, Togawa A, Matsui C, Arita K, Katahira-Tayama S, Sato T, Yamauchi E, Oda Y, Takai Y (2009) Synaptic activity prompts gamma-secretase-mediated cleavage of EphA4 and dendritic spine formation. J Cell Biol 185:551–564

    Article  PubMed  CAS  Google Scholar 

  246. Lin KT, Sloniowski S, Ethell DW, Ethell IM (2008) Ephrin-B2-induced cleavage of EphB2 receptor is mediated by matrix metalloproteinases to trigger cell repulsion. J Biol Chem 283:28969–28979

    Article  PubMed  CAS  Google Scholar 

  247. Pascall JC, Brown KD (2004) Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL2. Biochem Biophys Res Commun 317:244–252

    Article  PubMed  CAS  Google Scholar 

  248. Marston DJ, Dickinson S, Nobes CD (2003) Rac-dependent trans-endocytosis of ephrinBs regulates Eph–ephrin contact repulsion. Nat Cell Biol 5:879–888

    Article  PubMed  CAS  Google Scholar 

  249. Zimmer M, Palmer A, Kohler J, Klein R (2003) EphB–ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat Cell Biol 5:869–878

    Article  PubMed  CAS  Google Scholar 

  250. Kasemeier-Kulesa JC, Bradley R, Pasquale EB, Lefcort F, Kulesa PM (2006) Eph/ephrins and N-cadherin coordinate to control the pattern of sympathetic ganglia. Development 133:4839–4847

    Article  PubMed  CAS  Google Scholar 

  251. Orsulic S, Kemler R (2000) Expression of Eph receptors and ephrins is differentially regulated by E-cadherin. J Cell Sci 113:1793–1802

    PubMed  CAS  Google Scholar 

  252. Hess AR, Seftor EA, Gruman LM, Kinch MS, Seftor RE, Hendrix MJ (2006) VE-cadherin regulates EphA2 in aggressive melanoma cells through a novel signaling pathway: implications for vasculogenic mimicry. Cancer Biol Ther 5:228–233

    Article  PubMed  CAS  Google Scholar 

  253. van de Wetering M, Sancho E, Verweij C, de Lau W, Oving I, Hurlstone A, van der Horn K, Batlle E, Coudreuse D, Haramis AP, Tjon-Pon-Fong M, Moerer P, van den Born M, Soete G, Pals S, Eilers M, Medema R, Clevers H (2002) The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. Cell 111:241–250

    Article  PubMed  Google Scholar 

  254. Solanas G, Cortina C, Sevillano M, Batlle E (2011) Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling. Nat Cell Biol 13:1100–1107

    Article  PubMed  CAS  Google Scholar 

  255. Walker-Daniels J, Hess AR, Hendrix MJ, Kinch MS (2003) Differential regulation of EphA2 in normal and malignant cells. Am J Pathol 162:1037–1042

    Article  PubMed  CAS  Google Scholar 

  256. Yuan W, Chen Z, Wu S, Ge J, Chang S, Wang X, Chen J (2009) Expression of EphA2 and E-cadherin in gastric cancer: correlated with tumor progression and lymphogenous metastasis. Pathol Oncol Res 15:473–478

    Article  PubMed  CAS  Google Scholar 

  257. Miao H, Strebhardt K, Pasquale EB, Shen TL, Guan JL, Wang B (2005) 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 280:923–932

    Article  PubMed  CAS  Google Scholar 

  258. Bourgin C, Murai KK, Richter M, Pasquale EB (2007) The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. J Cell Biol 178:1295–1307

    Article  PubMed  CAS  Google Scholar 

  259. Miao H, Burnett E, Kinch M, Simon E, Wang B (2000) Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nat Cell Biol 2:62–69

    Article  PubMed  CAS  Google Scholar 

  260. Miao H, Li DQ, Mukherjee A, Guo H, Petty A, Cutter J, Basilion JP, Sedor J, Wu J, Danielpour D, Sloan AE, Cohen ML, Wang B (2009) EphA2 mediates ligand-dependent inhibition and ligand-independent promotion of cell migration and invasion via a reciprocal regulatory loop with Akt. Cancer Cell 16:9–20

    Article  PubMed  CAS  Google Scholar 

  261. Masuda J, Usui R, Maru Y (2008) Fibronectin type I repeat is a nonactivating ligand for EphA1 and inhibits ATF3-dependent angiogenesis. J Biol Chem 283:13148–13155

    Article  PubMed  CAS  Google Scholar 

  262. Nagashima K, Endo A, Ogita H, Kawana A, Yamagishi A, Kitabatake A, Matsuda M, Mochizuki N (2002) Adaptor protein Crk is required for ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells. Mol Biol Cell 13:4231–4242

    Article  PubMed  CAS  Google Scholar 

  263. Huang X, Wu D, Jin H, Stupack D, Wang JY (2008) Induction of cell retraction by the combined actions of Abl-CrkII and Rho-ROCK1 signaling. J Cell Biol 183:711–723

    Article  PubMed  CAS  Google Scholar 

  264. Li W, Fan J, Woodley DT (2001) Nck/Dock: an adapter between cell surface receptors and the actin cytoskeleton. Oncogene 20:6403–6417

    Article  PubMed  CAS  Google Scholar 

  265. Holland SJ, Gale NW, Gish GD, Roth RA, Songyang Z, Cantley LC, Henkemeyer M, Yancopoulos GD, Pawson T (1997) Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. EMBO J 16:3877–3888

    Article  PubMed  CAS  Google Scholar 

  266. Stein E, Huynh-Do U, Lane AA, Cerretti DP, Daniel TO (1998) Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J Biol Chem 273:1303–1308

    Article  PubMed  CAS  Google Scholar 

  267. Vindis C, Teli T, Cerretti DP, Turner CE, Huynh-Do U (2004) EphB1-mediated cell migration requires the phosphorylation of paxillin at Tyr-31/Tyr-118. J Biol Chem 279:27965–27970

    Article  PubMed  CAS  Google Scholar 

  268. Fawcett JP, Georgiou J, Ruston J, Bladt F, Sherman A, Warner N, Saab BJ, Scott R, Roder JC, Pawson T (2007) Nck adaptor proteins control the organization of neuronal circuits important for walking. Proc Natl Acad Sci USA 104:20973–20978

    Article  PubMed  CAS  Google Scholar 

  269. Hu T, Shi G, Larose L, Rivera GM, Mayer BJ, Zhou R (2009) Regulation of process retraction and cell migration by EphA3 is mediated by the adaptor protein Nck1. Biochemistry 48:6369–6378

    Article  PubMed  CAS  Google Scholar 

  270. Noren NK, Pasquale EB (2004) Eph receptor-ephrin bidirectional signals that target Ras and Rho proteins. Cell Signal 16:655–666

    Article  PubMed  CAS  Google Scholar 

  271. Jaffe AB, Hall A (2005) Rho GTPases: biochemistry and biology. Annu Rev Cell Dev Biol 21:247–269

    Article  PubMed  CAS  Google Scholar 

  272. Moeller ML, Shi Y, Reichardt LF, Ethell IM (2006) EphB receptors regulate dendritic spine morphogenesis through the recruitment/phosphorylation of focal adhesion kinase and RhoA activation. J Biol Chem 281:1587–1598

    Article  PubMed  CAS  Google Scholar 

  273. Shi Y, Pontrello CG, DeFea KA, Reichardt LF, Ethell IM (2009) Focal adhesion kinase acts downstream of EphB receptors to maintain mature dendritic spines by regulating cofilin activity. J Neurosci 29:8129–8142

    Article  PubMed  CAS  Google Scholar 

  274. Wahl S, Barth H, Ciossek T, Aktories K, Mueller BK (2000) Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J Cell Biol 149:263–270

    Article  PubMed  CAS  Google Scholar 

  275. Yamazaki T, Masuda J, Omori T, Usui R, Akiyama H, Maru Y (2009) EphA1 interacts with integrin-linked kinase and regulates cell morphology and motility. J Cell Sci 122:243–255

    Article  PubMed  CAS  Google Scholar 

  276. Wickstrom SA, Lange A, Montanez E, Fassler R (2010) The ILK/PINCH/parvin complex: the kinase is dead, long live the pseudokinase! EMBO J 29:281–291

    Article  PubMed  CAS  Google Scholar 

  277. Groeger G, Nobes CD (2007) Co-operative Cdc42 and Rho signalling mediates ephrinB-triggered endothelial cell retraction. Biochem J 404:23–29

    Article  PubMed  CAS  Google Scholar 

  278. Irie F, Yamaguchi Y (2002) EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. Nat Neurosci 5:1117–1118

    Article  PubMed  CAS  Google Scholar 

  279. Bisson N, Poitras L, Mikryukov A, Tremblay ML, Moss T (2007) EphA4 signaling regulates blastomere adhesion in the Xenopus embryo by recruiting Pak1 to suppress Cdc42 function. Mol Biol Cell 18:1030–1043

    Article  PubMed  CAS  Google Scholar 

  280. Jurney WM, Gallo G, Letourneau PC, McLoon SC (2002) Rac1-mediated endocytosis during ephrin-A2- and semaphorin 3A-induced growth cone collapse. J Neurosci 22:6019–6028

    PubMed  CAS  Google Scholar 

  281. Ostman A, Frijhoff J, Sandin A, Bohmer FD (2011) Regulation of protein tyrosine phosphatases by reversible oxidation. J Biochem 150:345–356

    Article  PubMed  CAS  Google Scholar 

  282. Chiarugi P, Pani G, Giannoni E, Taddei L, Colavitti R, Raugei G, Symons M, Borrello S, Galeotti T, Ramponi G (2003) Reactive oxygen species as essential mediators of cell adhesion: the oxidative inhibition of a FAK tyrosine phosphatase is required for cell adhesion. J Cell Biol 161:933–944

    Article  PubMed  CAS  Google Scholar 

  283. Buricchi F, Giannoni E, Grimaldi G, Parri M, Raugei G, Ramponi G, Chiarugi P (2007) Redox regulation of ephrin/integrin cross-talk. Cell Adh Migr 1:33–42

    PubMed  Google Scholar 

  284. Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, Katoh H (2010) Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol 190:461–477

    Article  PubMed  CAS  Google Scholar 

  285. Sahin M, Greer PL, Lin MZ, Poucher H, Eberhart J, Schmidt S, Wright TM, Shamah SM, O’Connell S, Cowan CW, Hu L, Goldberg JL, Debant A, Corfas G, Krull CE, Greenberg ME (2005) Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 46:191–204

    Article  PubMed  CAS  Google Scholar 

  286. Shamah SM, Lin MZ, Goldberg JL, Estrach S, Sahin M, Hu L, Bazalakova M, Neve RL, Corfas G, Debant A, Greenberg ME (2001) EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell 105:233–244

    Article  PubMed  CAS  Google Scholar 

  287. Knoll B, Drescher U (2004) Src family kinases are involved in EphA receptor-mediated retinal axon guidance. J Neurosci 24:6248–6257

    Article  PubMed  CAS  Google Scholar 

  288. Ogita H, Kunimoto S, Kamioka Y, Sawa H, Masuda M, Mochizuki N (2003) EphA4-mediated Rho activation via Vsm-RhoGEF expressed specifically in vascular smooth muscle cells. Circ Res 93(1):23–31

    Google Scholar 

  289. Cowan CW, Shao YR, Sahin M, Shamah SM, Lin MZ, Greer PL, Gao S, Griffith EC, Brugge JS, Greenberg ME (2005) Vav family GEFs link activated Ephs to endocytosis and axon guidance. Neuron 46:205–217

    Article  PubMed  CAS  Google Scholar 

  290. Hunter SG, Zhuang G, Brantley-Sieders D, Swat W, Cowan CW, Chen J (2006) Essential role of Vav family guanine nucleotide exchange factors in EphA receptor-mediated angiogenesis. Mol Cell Biol 26:4830–4842

    Article  PubMed  CAS  Google Scholar 

  291. Tanaka M, Ohashi R, Nakamura R, Shinmura K, Kamo T, Sakai R, Sugimura H (2004) Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2. EMBO J 23:1075–1088

    Article  PubMed  CAS  Google Scholar 

  292. Beg AA, Sommer JE, Martin JH, Scheiffele P (2007) alpha2-Chimaerin is an essential EphA4 effector in the assembly of neuronal locomotor circuits. Neuron 55:768–778

    Article  PubMed  CAS  Google Scholar 

  293. Iwasato T, Katoh H, Nishimaru H, Ishikawa Y, Inoue H, Saito YM, Ando R, Iwama M, Takahashi R, Negishi M, Itohara S (2007) Rac-GAP alpha-chimerin regulates motor-circuit formation as a key mediator of EphrinB3/EphA4 forward signaling. Cell 130:742–753

    Article  PubMed  CAS  Google Scholar 

  294. Shi L, Fu WY, Hung KW, Porchetta C, Hall C, Fu AK, Ip NY (2007) Alpha2-chimaerin interacts with EphA4 and regulates EphA4-dependent growth cone collapse. Proc Natl Acad Sci USA 104:16347–16352

    Article  PubMed  CAS  Google Scholar 

  295. Wegmeyer H, Egea J, Rabe N, Gezelius H, Filosa A, Enjin A, Varoqueaux F, Deininger K, Schnutgen F, Brose N, Klein R, Kullander K, Betz A (2007) EphA4-dependent axon guidance is mediated by the RacGAP alpha2-chimaerin. Neuron 55:756–767

    Article  PubMed  CAS  Google Scholar 

  296. Ho SK, Kovacevic N, Henkelman RM, Boyd A, Pawson T, Henderson JT (2009) EphB2 and EphA4 receptors regulate formation of the principal inter-hemispheric tracts of the mammalian forebrain. Neuroscience 160:784–795

    Article  PubMed  CAS  Google Scholar 

  297. Takeuchi S, Yamaki N, Iwasato T, Negishi M, Katoh H (2009) [beta]2-Chimaerin binds to EphA receptors and regulates cell migration. FEBS Lett 583:1237–1242

    Article  PubMed  CAS  Google Scholar 

  298. Fang WB, Ireton RC, Zhuang G, Takahashi T, Reynolds A, Chen J (2008) Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J Cell Sci 121:358–368

    Article  PubMed  CAS  Google Scholar 

  299. Kinbara K, Goldfinger LE, Hansen M, Chou F-L, Ginsberg MH (2003) Ras GTPases: integrins’ friends or foes? Nat Rev Mol Cell Biol 4:767–778

    PubMed  CAS  Google Scholar 

  300. Elowe S, Holland SJ, Kulkarni S, Pawson T (2001) 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 21:7429–7441

    Article  PubMed  CAS  Google Scholar 

  301. Tong J, Elowe S, Nash P, Pawson T (2003) Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAPK signaling and biological activity. J Biol Chem 278:6111–6119

    Article  PubMed  CAS  Google Scholar 

  302. Zou JX, Wang B, Kalo MS, Zisch AH, Pasquale EB, Ruoslahti E (1999) An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci USA 96:13813–13818

    Article  PubMed  CAS  Google Scholar 

  303. Dail M, Richter M, Godement P, Pasquale EB (2006) Eph receptors inactivate R-Ras through different mechanisms to achieve cell repulsion. J Cell Sci 119:1244–1254

    Article  PubMed  CAS  Google Scholar 

  304. Nakada M, Niska JA, Tran NL, McDonough WS, Berens ME (2005) EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. Am J Pathol 167:565–576

    Article  PubMed  CAS  Google Scholar 

  305. Roselli S, Wallez Y, Wang L, Vervoort V, Pasquale EB (2010) The SH2 domain protein Shep1 regulates the in vivo signaling function of the scaffolding protein Cas. Cell Signal 22:1745–1752

    Article  PubMed  CAS  Google Scholar 

  306. Dodelet VC, Pazzagli C, Zisch AH, Hauser CA, Pasquale EB (1999) A novel signaling intermediate, SHEP1, directly couples Eph receptors to R-Ras and Rap1A. J Biol Chem 274:31941–31946

    Article  PubMed  CAS  Google Scholar 

  307. Riedl JA, Brandt DT, Batlle E, Price LS, Clevers H, Bos JL (2005) Down-regulation of Rap1 activity is involved in ephrinB1-induced cell contraction. Biochem J 389:465–469

    Article  PubMed  CAS  Google Scholar 

  308. Richter M, Murai KK, Bourgin C, Pak DT, Pasquale EB (2007) The EphA4 receptor regulates neuronal morphology through SPAR-mediated inactivation of Rap GTPases. J Neurosci 27:14205–14215

    Article  PubMed  CAS  Google Scholar 

  309. Aoki M, Yamashita T, Tohyama M (2004) EphA receptors direct the differentiation of mammalian neural precursor cells through a mitogen-activated protein kinase-dependent pathway. J Biol Chem 279:32643–32650

    Article  PubMed  CAS  Google Scholar 

  310. Davy A, Soriano P (2005) Ephrin signaling in vivo: look both ways. Dev Dyn 232:1–10

    Article  PubMed  CAS  Google Scholar 

  311. Egea J, Klein R (2007) Bidirectional Eph–ephrin signaling during axon guidance. Trends Cell Biol 17:230–238

    Article  PubMed  CAS  Google Scholar 

  312. Marquardt T, Shirasaki R, Ghosh S, Andrews SE, Carter N, Hunter T, Pfaff SL (2005) Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell 121:127–139

    Article  PubMed  CAS  Google Scholar 

  313. Campbell TN, Davy A, Liu Y, Arcellana-Panlilio M, Robbins SM (2008) Distinct membrane compartmentalization and signaling of ephrin-A5 and ephrin-B1. Biochem Biophys Res Commun 375:362–366

    Article  PubMed  CAS  Google Scholar 

  314. Gauthier LR, Robbins SM (2003) Ephrin signaling: one raft to rule them all? One raft to sort them? One raft to spread their call and in signaling bind them? Life Sci 74:207–216

    Article  PubMed  CAS  Google Scholar 

  315. Davy A, Gale NW, Murray EW, Klinghoffer RA, Soriano P, Feuerstein C, Robbins SM (1999) Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Genes Dev 13:3125–3135

    Article  PubMed  CAS  Google Scholar 

  316. Kao TJ, Kania A (2011) Ephrin-mediated cis-attenuation of Eph receptor signaling is essential for spinal motor axon guidance. Neuron 71:76–91

    Article  PubMed  CAS  Google Scholar 

  317. Bruckner K, Pasquale EB, Klein R (1997) Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275:1640–1643

    Article  PubMed  CAS  Google Scholar 

  318. Holland SJ, Gale NW, Mbamalu G, Yancopoulos GD, Henkemeyer M, Pawson T (1996) Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 383:722–725

    Article  PubMed  CAS  Google Scholar 

  319. Palmer A, Zimmer M, Erdmann KS, Eulenburg V, Porthin A, Heumann R, Deutsch U, Klein R (2002) EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Mol Cell 9:725–737

    Article  PubMed  CAS  Google Scholar 

  320. Chong LD, Park EK, Latimer E, Friesel R, Daar IO (2000) Fibroblast growth factor receptor-mediated rescue of x-ephrin B1-induced cell dissociation in Xenopus embryos. Mol Cell Biol 20:724–734

    Article  PubMed  CAS  Google Scholar 

  321. Cowan CA, Henkemeyer M (2001) The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413:174–179

    Article  PubMed  CAS  Google Scholar 

  322. Bruckner K, Pablo Labrador J, Scheiffele P, Herb A, Seeburg PH, Klein R (1999) EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22:511–524

    Article  PubMed  CAS  Google Scholar 

  323. Lin D, Gish GD, Songyang Z, Pawson T (1999) The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif. J Biol Chem 274:3726–3733

    Article  PubMed  CAS  Google Scholar 

  324. Lu Q, Sun EE, Klein RS, Flanagan JG (2001) Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105:69–79

    Article  PubMed  CAS  Google Scholar 

  325. Bochenek ML, Dickinson S, Astin JW, Adams RH, Nobes CD (2010) Ephrin-B2 regulates endothelial cell morphology and motility independently of Eph-receptor binding. J Cell Sci 123:1235–1246

    Article  PubMed  CAS  Google Scholar 

  326. Dravis C, Henkemeyer M (2011) Ephrin-B reverse signaling controls septation events at the embryonic midline through separate tyrosine phosphorylation-independent signaling avenues. Dev Biol 355:138–151

    Article  PubMed  CAS  Google Scholar 

  327. Xu NJ, Sun S, Gibson JR, Henkemeyer M (2011) A dual shaping mechanism for postsynaptic ephrin-B3 as a receptor that sculpts dendrites and synapses. Nat Neurosci 14:1421–1429

    Article  PubMed  CAS  Google Scholar 

  328. Vihanto MM, Plock J, Erni D, Frey BM, Frey FJ, Huynh-Do U (2005) Hypoxia up-regulates expression of Eph receptors and ephrins in mouse skin. Faseb J 19:1689–1691

    PubMed  CAS  Google Scholar 

  329. Bonaparte MI, Dimitrov AS, Bossart KN, Crameri G, Mungall BA, Bishop KA, Choudhry V, Dimitrov DS, Wang LF, Eaton BT, Broder CC (2005) Ephrin-B2 ligand is a functional receptor for Hendra virus and Nipah virus. Proc Natl Acad Sci USA 102:10652–10657

    Article  PubMed  CAS  Google Scholar 

  330. Negrete OA, Levroney EL, Aguilar HC, Bertolotti-Ciarlet A, Nazarian R, Tajyar S, Lee B (2005) EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature 436:401–405

    PubMed  CAS  Google Scholar 

  331. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L, Davis C, Mee CJ, Turek M, Gorke S, Royer C, Fischer B, Zahid MN, Lavillette D, Fresquet J, Cosset FL, Rothenberg SM, Pietschmann T, Patel AH, Pessaux P, Doffoel M, Raffelsberger W, Poch O, McKeating JA, Brino L, Baumert TF (2011) EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 17:589–595

    Article  PubMed  CAS  Google Scholar 

  332. Holen HL, Zernichow L, Fjelland KE, Evenroed IM, Prydz K, Tveit H, Aasheim HC (2011) Ephrin-B3 binds to a sulfated cell-surface receptor. Biochem J 433:215–223

    Article  PubMed  CAS  Google Scholar 

  333. Irie F, Okuno M, Matsumoto K, Pasquale EB, Yamaguchi Y (2008) Heparan sulfate regulates ephrin-A3/EphA receptor signaling. Proc Natl Acad Sci USA 105:12307–12312

    Article  PubMed  CAS  Google Scholar 

  334. Davy A, Robbins SM (2000) Ephrin-A5 modulates cell adhesion and morphology in an integrin-dependent manner. EMBO J 19:5396–5405

    Article  PubMed  CAS  Google Scholar 

  335. Holen HL, Shadidi M, Narvhus K, Kjosnes O, Tierens A, Aasheim HC (2008) Signaling through ephrin-A ligand leads to activation of Src-family kinases, Akt phosphorylation, and inhibition of antigen receptor-induced apoptosis. J Leukoc Biol 84(4):1183–1191

    Google Scholar 

  336. Lim YS, McLaughlin T, Sung TC, Santiago A, Lee KF, O’Leary DD (2008) p75(NTR) mediates ephrin-A reverse signaling required for axon repulsion and mapping. Neuron 59:746–758

    Article  PubMed  CAS  Google Scholar 

  337. Marler KJ, Becker-Barroso E, Martinez A, Llovera M, Wentzel C, Poopalasundaram S, Hindges R, Soriano E, Comella J, Drescher U (2008) A TrkB/EphrinA interaction controls retinal axon branching and synaptogenesis. J Neurosci 28:12700–12712

    Article  PubMed  CAS  Google Scholar 

  338. Meyer S, Hafner C, Guba M, Flegel S, Geissler EK, Becker B, Koehl GE, Orso E, Landthaler M, Vogt T (2005) Ephrin-B2 overexpression enhances integrin-mediated ECM-attachment and migration of B16 melanoma cells. Int J Oncol 27:1197–1206

    PubMed  CAS  Google Scholar 

  339. Huynh-Do U, Vindis C, Liu H, Cerretti DP, McGrew JT, Enriquez M, Chen J, Daniel TO (2002) Ephrin-B1 transduces signals to activate integrin-mediated migration, attachment and angiogenesis. J Cell Sci 115:3073–3081

    PubMed  CAS  Google Scholar 

  340. Xu Z, Lai KO, Zhou HM, Lin SC, Ip NY (2003) Ephrin-B1 reverse signaling activates JNK through a novel mechanism that is independent of tyrosine phosphorylation. J Biol Chem 278:24767–24775

    Article  PubMed  CAS  Google Scholar 

  341. Julich D, Mould AP, Koper E, Holley SA (2009) Control of extracellular matrix assembly along tissue boundaries via integrin and Eph/Ephrin signaling. Development 136:2913–2921

    Article  PubMed  CAS  Google Scholar 

  342. Prevost N, Woulfe DS, Tognolini M, Tanaka T, Jian W, Fortna RR, Jiang H, Brass LF (2004) Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion, and aggregation via effector pathways that do not require phosphorylation of ephrinB1. Blood 103:1348–1355

    Article  PubMed  CAS  Google Scholar 

  343. Lee HS, Bong YS, Moore KB, Soria K, Moody SA, Daar IO (2006) Dishevelled mediates ephrinB1 signalling in the eye field through the planar cell polarity pathway. Nat Cell Biol 8:55–63

    Article  PubMed  CAS  Google Scholar 

  344. Xu NJ, Henkemeyer M (2009) Ephrin-B3 reverse signaling through Grb4 and cytoskeletal regulators mediates axon pruning. Nat Neurosci 12:268–276

    Article  PubMed  CAS  Google Scholar 

  345. Nakada M, Drake KL, Nakada S, Niska JA, Berens ME (2006) Ephrin-B3 ligand promotes glioma invasion through activation of Rac1. Cancer Res 66:8492–8500

    Article  PubMed  CAS  Google Scholar 

  346. Steinle JJ, Meininger CJ, Chowdhury U, Wu G, Granger HJ (2003) Role of ephrin B2 in human retinal endothelial cell proliferation and migration. Cell Signal 15:1011–1017

    Article  PubMed  CAS  Google Scholar 

  347. Steinle JJ, Meininger CJ, Forough R, Wu G, Wu MH, Granger HJ (2002) Eph B4 receptor signaling mediates endothelial cell migration and proliferation via the phosphatidylinositol 3-kinase pathway. J Biol Chem 277:43830–43835

    Article  PubMed  CAS  Google Scholar 

  348. Watanabe T, Sato Y, Saito D, Tadokoro R, Takahashi Y (2009) EphrinB2 coordinates the formation of a morphological boundary and cell epithelialization during somite segmentation. Proc Natl Acad Sci USA 106:7467–7472

    Article  PubMed  CAS  Google Scholar 

  349. Lee HS, Mood K, Battu G, Ji YJ, Singh A, Daar IO (2009) Fibroblast growth factor receptor-induced phosphorylation of ephrinB1 modulates its interaction with dishevelled. Mol Biol Cell 20:124–133

    Article  PubMed  CAS  Google Scholar 

  350. Moore KB, Mood K, Daar IO, Moody SA (2004) Morphogenetic movements underlying eye field formation require interactions between the FGF and ephrinB1 signaling pathways. Dev Cell 6:55–67

    Article  PubMed  CAS  Google Scholar 

  351. Tanaka M, Kamata R, Sakai R (2005) Phosphorylation of ephrin-B1 via the interaction with claudin following cell-cell contact formation. EMBO J 24:3700–3711

    Article  PubMed  CAS  Google Scholar 

  352. Lee HS, Nishanian TG, Mood K, Bong YS, Daar IO (2008) EphrinB1 controls cell-cell junctions through the Par polarity complex. Nat Cell Biol 10:979–986

    Article  PubMed  CAS  Google Scholar 

  353. Lee HS, Daar IO (2009) EphrinB reverse signaling in cell-cell adhesion: is it just par for the course? Cell Adh Migr 3:250–255

    Article  PubMed  Google Scholar 

  354. Campbell TN, Attwell S, Arcellana-Panlilio M, Robbins SM (2006) Ephrin A5 expression promotes invasion and transformation of murine fibroblasts. Biochem Biophys Res Commun 350:623–628

    Article  PubMed  CAS  Google Scholar 

  355. Jiang G, Freywald T, Webster J, Kozan D, Geyer R, DeCoteau J, Narendran A, Freywald A (2008) In human leukemia cells ephrin-B-induced invasive activity is supported by Lck and is associated with reassembling of lipid raft signaling complexes. Mol Cancer Res 6:291–305

    Article  PubMed  CAS  Google Scholar 

  356. Nakada M, Anderson EM, Demuth T, Nakada S, Reavie LB, Drake KL, Hoelzinger DB, Berens ME (2009) The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion. Int J Cancer 126:1155–1165

    Google Scholar 

  357. Tanaka M, Sasaki K, Kamata R, Sakai R (2007) The C-terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells. J Cell Sci 120:2179–2189

    Article  PubMed  CAS  Google Scholar 

  358. de Saint-Vis B, Bouchet C, Gautier G, Valladeau J, Caux C, Garrone P (2003) Human dendritic cells express neuronal Eph receptor tyrosine kinases: role of EphA2 in regulating adhesion to fibronectin. Blood 102:4431–4440

    Article  PubMed  CAS  Google Scholar 

  359. Becker E, Huynh-Do U, Holland S, Pawson T, Daniel TO, Skolnik EY (2000) Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol Cell Biol 20:1537–1545

    Article  PubMed  CAS  Google Scholar 

  360. Parri M, Taddei ML, Bianchini F, Calorini L, Chiarugi P (2009) EphA2 reexpression prompts invasion of melanoma cells shifting from mesenchymal to amoeboid-like motility style. Cancer Res 69:2072–2081

    Article  PubMed  CAS  Google Scholar 

  361. Parri M, Buricchi F, Giannoni E, Grimaldi G, Mello T, Raugei G, Ramponi G, Chiarugi P (2007) EphrinA1 activates a Src/focal adhesion kinase-mediated motility response leading to rho-dependent actino/myosin contractility. J Biol Chem 282:19619–19628

    Article  PubMed  CAS  Google Scholar 

  362. Zimmer G, Kastner B, Weth F, Bolz J (2007) Multiple effects of ephrin-A5 on cortical neurons are mediated by SRC family kinases. J Neurosci 27:5643–5653

    Article  PubMed  CAS  Google Scholar 

  363. Vindis C, Cerretti DP, Daniel TO, Huynh-Do U (2003) EphB1 recruits c-Src and p52Shc to activate MAPK/ERK and promote chemotaxis. J Cell Biol 162:661–671

    Article  PubMed  CAS  Google Scholar 

  364. Clifford N, Smith LM, Powell J, Gattenlohner S, Marx A, O’Connor R (2008) The EphA3 receptor is expressed in a subset of rhabdomyosarcoma cell lines and suppresses cell adhesion and migration. J Cell Biochem 105:1250–1259

    Article  PubMed  CAS  Google Scholar 

  365. Hjorthaug HS, Aasheim HC (2007) Ephrin-A1 stimulates migration of CD8+CCR7+ T lymphocytes. Eur J Immunol 37:2326–2336

    Article  PubMed  CAS  Google Scholar 

  366. Miao H, Nickel CH, Cantley LG, Bruggeman LA, Bennardo LN, Wang B (2003) EphA kinase activation regulates HGF-induced epithelial branching morphogenesis. J Cell Biol 162:1281–1292

    Article  PubMed  CAS  Google Scholar 

  367. Gallo G, Yee HF Jr, Letourneau PC (2002) Actin turnover is required to prevent axon retraction driven by endogenous actomyosin contractility. J Cell Biol 158:1219–1228

    Article  PubMed  CAS  Google Scholar 

  368. Puschmann TB, Turnley AM (2010) Eph receptor tyrosine kinases regulate astrocyte cytoskeletal rearrangement and focal adhesion formation. J Neurochem 113:881–894

    Article  PubMed  CAS  Google Scholar 

  369. Ogawa K, Wada H, Okada N, Harada I, Nakajima T, Pasquale EB, Tsuyama S (2006) EphB2 and ephrin-B1 expressed in the adult kidney regulate the cytoarchitecture of medullary tubule cells through Rho family GTPases. J Cell Sci 119:559–570

    Article  PubMed  CAS  Google Scholar 

  370. Yang NY, Pasquale EB, Owen LB, Ethell IM (2006) The EphB4 receptor-tyrosine kinase promotes the migration of melanoma cells through Rho-mediated actin cytoskeleton reorganization. J Biol Chem 281:32574–32586

    Article  PubMed  CAS  Google Scholar 

  371. Tolias KF, Bikoff JB, Kane CG, Tolias CS, Hu L, Greenberg ME (2007) The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. Proc Natl Acad Sci USA 104:7265–7270

    Article  PubMed  CAS  Google Scholar 

  372. Huai J, Drescher U (2001) An ephrin-A-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120 kDa protein. J Biol Chem 276:6689–6694

    Article  PubMed  CAS  Google Scholar 

  373. Hamada K, Oike Y, Ito Y, Maekawa H, Miyata K, Shimomura T, Suda T (2003) Distinct roles of ephrin-B2 forward and EphB4 reverse signaling in endothelial cells. Arterioscler Thromb Vasc Biol 23:190–197

    Article  PubMed  CAS  Google Scholar 

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  1. Eva Nievergall

    Present address: Haematology Department, SA Pathology, Frome Road, Adelaide, SA, 5000, Australia

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  1. Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, VIC, 3800, Australia

    Eva Nievergall, Martin Lackmann & Peter W. Janes

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Nievergall, E., Lackmann, M. & Janes, P.W. Eph-dependent cell-cell adhesion and segregation in development and cancer. Cell. Mol. Life Sci. 69, 1813–1842 (2012). https://doi.org/10.1007/s00018-011-0900-6

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