Mechanisms and functions of eph and ephrin signalling
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Mellitzer, G., Xu, Q. & Wilkinson, D. G. Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77–81 (1999).
Holland, S. J. et al. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 383, 722–725 (1996).
Bruckner, K., Pasquale, E. B. & Klein, R. Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275, 1640–1643 (1997).References 2 and 3 provide the first biochemical evidence for tyrosine phosphorylation of the ephrinB cytoplasmic tail, which indicates reverse signalling.
Davis, S. et al. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266, 816–819 (1994).
Kalo, M. S. & Pasquale, E. B. Multiple in vivo tyrosine phosphorylation sites in EphB receptors. Biochemistry 38, 14396–14408 (1999).
Binns, K. L., Taylor, P. P., Sicheri, F., Pawson, T. & Holland, S. J. 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 (2000).
Zisch, A. H. et al. Replacing two conserved tyrosines of the EphB2 receptor with glutamic acid prevents binding of SH2 domains without abrogating kinase activity and biological responses. Oncogene 19, 177–187 (2000).
Kullander, K. et al. Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 29, 73–84 (2001).This study showed that an Eph receptor can have kinase-dependent and kinase-independent functions in axon-tract formation in vivo.
Wybenga-Groot, L. E. et al. Structural basis for autoinhibition of the EphB2 receptor tyrosine kinase by the unphosphorylated juxtamembrane region. Cell 106, 745–757 (2001).This article contains structural data on the cytoplasmic tail of EphB2 and a model that explains how Eph-receptor kinase activity is autoinhibited by the juxtamembrane domain.
Baxter, R. M., Secrist, J. P., Vaillancourt, R. R. & Kazlauskas, A. Full activation of the platelet-derived growth factor β-receptor kinase involves multiple events. J. Biol. Chem. 273, 17050–17055 (1998).
Postigo, A. et al. Distinct requirements for TrkB and TrkC signaling in target innervation by sensory neurons. Genes Dev. 16, 633–645 (2002).
Pawson, T. & Scott, J. D. Signaling through scaffold, anchoring, and adaptor proteins. Science 278, 2075–2080 (1997).
Van Etten, R. A. Cycling, stressed-out and nervous: cellular functions of c-Abl. Trends Cell Biol. 9, 179–186 (1999).
Yu, H. H., Zisch, A. H., Dodelet, V. C. & Pasquale, E. B. Multiple signaling interactions of Abl and Arg kinases with the EphB2 receptor. Oncogene 20, 3995–4006 (2001).
Plattner, R., Kadlec, L., DeMali, K. A., Kazlauskas, A. & Pendergast, A. M. c-Abl is activated by growth factors and Src family kinases and has a role in the cellular response to PDGF. Genes Dev. 13, 2400–2411 (1999).
Zisch, A. H., Kalo, M. S., Chong, L. D. & Pasquale, E. B. Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region. Oncogene 16, 2657–2670 (1998).
Koleske, A. J. et al. Essential roles for the Abl and Arg tyrosine kinases in neurulation. Neuron 21, 1259–1272 (1998).
Holmberg, J., Clarke, D. L. & Frisen, J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408, 203–206 (2000).
Kozma, R., Sarner, S., Ahmed, S. & Lim, L. Rho family GTPases and neuronal growth cone remodelling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol. Cell. Biol. 17, 1201–1211 (1997).
Shamah, S. M. et al. EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell 105, 233–244 (2001).This piece reports the identification of a new guanine nucleotide exchange factor, Ephexin, for Rho family GTPases as a downstream target of Eph receptors and provides a mechanism as to how Ephs regulate the actin cytoskeleton.
Wahl, S., Barth, H., Ciossek, T., Aktories, K. & Mueller, B. K. EphrinA5 induces collapse of growth cones by activating Rho and Rho kinase. J. Cell Biol. 149, 263–270 (2000).
Miao, H. et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/MAPK pathway. Nature Cell Biol. 3, 527–530 (2001).
Elowe, S., Holland, S. J., Kulkarni, S. & Pawson, T. Downregulation of the ras-mitogen-activated protein kinase pathway by the ephb2 receptor tyrosine kinase is required for ephrin-induced neurite retraction. Mol. Cell. Biol. 21, 7429–7441 (2001).
Brambilla, R. et al. Membrane-bound LERK2 ligand can signal through three different Eph-related receptor tyrosine kinases. EMBO J. 14, 3116–3126 (1995).
Lhotak, V. & Pawson, T. Biological and biochemical activities of a chimeric epidermal growth factor–Elk receptor tyrosine kinase. Mol. Cell. Biol. 13, 7071–7079 (1993).
Bruce, V., Olivieri, G., Eickelberg, O. & Miescher, G. C. Functional activation of EphA5 receptor does not promote cell proliferation in the aberrant EphA5 expressing human glioblastoma U-118 MG cell line. Brain Res. 821, 169–176 (1999).
Olivier, J. P. et al. A Drosophila SH2–SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell 73, 179–191 (1993).
Simon, M. A., Dodson, G. S. & Rubin, G. M. An SH3–SH2–SH3 protein is required for p21Ras1 activation and binds to sevenless and Sos proteins in vitro. Cell 73, 169–177 (1993).
Kolch, W. Meaningful relationships: the regulation of the Ras/Raf/MEK/ERK pathway by protein interactions. Biochem. J. 351, 289–305 (2000).
Schlaepfer, D. D. & Hunter, T. Integrin signalling and tyrosine phosphorylation: just the FAKs? Trends Cell Biol. 8, 151–157 (1998).
Zou, J. X. et al. An Eph receptor regulates integrin activity through R-Ras. Proc. Natl Acad. Sci. USA 96, 13813–13818 (1999).
Miao, H., Burnett, E., Kinch, M., Simon, E. & Wang, B. Activation of EphA2 kinase suppresses integrin function and causes focal-adhesion-kinase dephosphorylation. Nature Cell Biol. 2, 62–69 (2000).
Huynh-Do, U. et al. Surface densities of ephrinB1 determine EphB1-coupled activation of cell attachment through αvβ3 and α5β1 integrins. EMBO J. 18, 2165–2173 (1999).
Becker, E. et al. Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol. Cell. Biol. 20, 1537–1545 (2000).
Gu, C. & Park, S. The EphA8 receptor regulates integrin activity through p110γ phosphatidylinositol 3-kinase in a tyrosine kinase activity-independent manner. Mol. Cell. Biol. 21, 4579–4597 (2001).
Bruckner, K. & Klein, R. Signaling by Eph receptors and their ephrin ligands. Curr. Opin. Neurobiol. 8, 375–382 (1998).
Flanagan, J. G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurosci. 21, 309–345 (1998).
Wilkinson, D. G. Eph receptors and ephrins: regulators of guidance and assembly. Int. Rev. Cytol. 196, 177–244 (2000).
Henkemeyer, M. et al. Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell 86, 35–46 (1996).This paper provides the first genetic evidence for EphB2 (Nuk) having a kinase-independent role in axon-tract formation and suggested reverse signalling by ephrins.
Kalo, M. S., Yu, H. H. & Pasquale, E. B. In vivo tyrosine phosphorylation sites of activated ephrinB1 and ephB2 from neural tissue. J. Biol. Chem. 276, 38940–38948 (2001).
Palmer, A. et al. EphrinB phosphorylation and reverse signaling: regulation by Src kinases and PTP-BL phosphatase. Mol. Cell 9, 725–737 (2002).This article shows that Src-family kinases are required for ephrinB phosphorylation and angiogenic sprouting and indicates the presence of a switch mechanism from tyrosine-phosphorylation-dependent to PDZ-domain-dependent signalling.
Chong, L. D., Park, E. K., Latimer, E., Friesel, R. & Daar, I. O. Fibroblast growth factor receptor-mediated rescue of x-ephrin B1-induced cell dissociation in Xenopus embryos. Mol. Cell. Biol. 20, 724–734 (2000).
Torres, R. et al. PDZ proteins bind, cluster, and synaptically colocalize with Eph receptors and their ephrin ligands. Neuron 21, 1453–1463 (1998).
Bruckner, K. et al. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22, 511–524 (1999).
Lin, D., Gish, G. D., Songyang, Z. & Pawson, T. The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif. J. Biol. Chem. 274, 3726–3733 (1999).
Cowan, C. A. & Henkemeyer, M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413, 174–179 (2001).This study identified the adaptor Grb4 as an essential downstream effector of ephrinB reverse signalling.
Ribon, V., Herrera, R., Kay, B. K. & Saltiel, A. R. A role for CAP, a novel, multifunctional Src homology 3 domain-containing protein in formation of actin stress fibers and focal adhesions. J. Biol. Chem. 273, 4073–4080 (1998).
Coutinho, S. et al. Characterization of Grb4, an adapter protein interacting with Bcr-Abl. Blood 96, 618–624 (2000).
Dai, Z. & Pendergast, A. M. Abi-2, a novel SH3-containing protein interacts with the c-Abl tyrosine kinase and modulates c-Abl transforming activity. Genes Dev. 9, 2569–2582 (1995).
Shi, Y., Alin, K. & Goff, S. P. Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity. Genes Dev. 9, 2583–2597 (1995).
Lu, Q., Sun, E. E., Klein, R. S. & Flanagan, J. G. Ephrin-B reverse signaling is mediated by a novel PDZ–RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105, 69–79 (2001).This paper provides the first functional relevance for ephrinB interaction with PDZ-domain-containing proteins in the regulation of heterotrimeric G-protein signalling and neuronal migration.
Salcedo, R. et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1α. Am. J. Pathol. 154, 1125–1135 (1999).
Gupta, S. K., Lysko, P. G., Pillarisetti, K., Ohlstein, E. & Stadel, J. M. Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines. J. Biol. Chem. 273, 4282–4287 (1998).
Wang, X. et al. 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 (1999).This, and reference 62 , identified functions of the C. elegans Eph receptor VAB-1 and the corresponding ephrins. As for other genetic studies VAB-1 can have kinase-dependent and kinase-independent functions.
Davy, A. et al. Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Genes Dev. 13, 3125–3135 (1999).This study identified the Src-family kinase Fyn as an adaptor downstream of ephrinA signalling.
Davy, A. & Robbins, S. M. Ephrin-A5 modulates cell adhesion and morphology in an integrin-dependent manner. EMBO J. 19, 5396–5405 (2000).
Huai, J. & Drescher, U. 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 (2001).
Birgbauer, E., Cowan, C. A., Sretavan, D. W. & Henkemeyer, M. Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. Development 127, 1231–1241 (2000).
Birgbauer, E., Oster, S. F., Severin, C. G. & Sretavan, D. W. Retinal axon growth cones respond to EphB extracellular domains as inhibitory axon guidance cues. Development 128, 3041–3048 (2001).
George, S. E., Simokat, K., Hardin, J. & Chisholm, A. D. The VAB-1 Eph receptor tyrosine kinase functions in neural and epithelial morphogenesis in C. elegans. Cell 92, 633–643 (1998).
Dottori, M. et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc. Natl Acad. Sci. USA 95, 13248–13253 (1998).
Kullander, K. et al. Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes Dev. 15, 877–888 (2001).References 64 and 65 provide genetic data that ephrinB3 acts as a midline barrier for corticospinal-tract axons that express EphA4. Reference 65 further shows that the ephrinB3 cytoplasmic tail is not required for this function.
Yokoyama, N. et al. Forward signaling mediated by ephrin-B3 prevents contralateral corticospinal axons from recrossing the spinal cord midline. Neuron 29, 85–97 (2001).
Martone, M. E., Holash, J. A., Bayardo, A., Pasquale, E. B. & Ellisman, M. H. Immunolocalization of the receptor tyrosine kinase EphA4 in the adult rat central nervous system. Brain Res. 771, 238–250 (1997).
Stein, E. et al. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev. 12, 667–678 (1998).
Smalla, M. et al. Solution structure of the receptor tyrosine kinase EphB2 SAM domain and identification of two distinct homotypic interaction sites. Protein Sci. 8, 1954–1961 (1999).
Stapleton, D., Balan, I., Pawson, T. & Sicheri, F. The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization. Nature Struct. Biol. 6, 44–49 (1999).
Thanos, C. D., Goodwill, K. E. & Bowie, J. U. Oligomeric structure of the human EphB2 receptor SAM domain. Science 283, 833–836 (1999).
Cowan, C. A., Yokoyama, N., Bianchi, L. M., Henkemeyer, M. & Fritzsch, B. EphB2 guides axons at the midline and is necessary for normal vestibular function. Neuron 26, 417–430 (2000).
Dalva, M. B. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945–956 (2000).This is the first study to show a direct interaction between the EphB2 receptor and the NMDA-type glutamate receptor NR1 and indicates a possible role for EphB2 in synapse formation or function.
Takasu, M. A., Dalva, M. B., Zigmond, R. E. & Greenberg, M. E. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 295, 491–495 (2002).
Ethell, I. M. et al. EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31, 1001–1013 (2001).
Grunwald, I. C. et al. Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32, 1027–1040 (2001).
Henderson, J. T. et al. The receptor tyrosine kinase EphB2 regulates NMDA-dependent synaptic function. Neuron 32, 1041–1056 (2001).References 75 and 76 show a requirement for EphB2 in hippocampal synaptic plasticity, which is possibly linked to its interaction with NMDA receptors.
Xu, Q., Mellitzer, G., Robinson, V. & Wilkinson, D. G. In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins. Nature 399, 267–271 (1999).
Mellitzer, G., Xu, Q. & Wilkinson, D. G. Eph receptors and ephrins restrict cell intermingling and communication. Nature 400, 77–81 (1999).References 78 and 79 show ephrin–Eph bidirectional signalling in hindbrain-segment-boundary formation and in restriction of cell intermingling.
Adams, R. H. et al. The cytoplasmic domain of the ligand ephrinB2 is required for vascular morphogenesis but not cranial neural crest migration. Cell 104, 57–69 (2001).In vivo data that show the importance of the cytoplasmic domain of ephrinB2 for angiogenic remodelling.
Smith, A., Robinson, V., Patel, K. & Wilkinson, D. G. The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of branchial neural crest cells. Curr. Biol. 7, 561–570 (1997).
Wang, H. & Anderson, D. Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18, 383–396 (1997).
Krull, C. E. et al. Interactions of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration. Curr. Biol. 7, 571–580 (1997).
Gavin, A. C. et al. Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415, 141–147 (2002).
Ho, Y. et al. Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415, 180–183 (2002).
Sajjadi, F. G. & Pasquale, E. B. Five novel avian Eph-related tyrosine kinases are differentially expressed. Oncogene 8, 1807–1813 (1993).
Scully, A. L., McKeown, M. & Thomas, J. B. Isolation and characterization of Dek, a Drosophila eph receptor protein tyrosine kinase. Mol. Cell Neurosci. 13, 337–347 (1999).
Dai, Y. Drosophila melanogaster Ephrin mRNA, complete cds. In 'GenBank/EMBL/DDBJ', pp. AF216287. (1999).
Chin-Sang, I. D. et al. The ephrin VAB-2/EFN-1 functions in neuronal signaling to regulate epidermal morphogenesis in C. elegans. Cell 99, 781–790 (1999).
Orioli, D., Henkemeyer, M., Lemke, G., Klein, R. & Pawson, T. Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. EMBO J. 15, 6035–6049 (1996).
O'Leary, D. D. & Wilkinson, D. G. Eph receptors and ephrins in neural development. Curr. Opin. Neurobiol. 9, 65–73 (1999).
Knoll, B., Zarbalis, K., Wurst, W. & Drescher, U. A role for the EphA family in the topographic targeting of vomeronasal axons. Development 128, 895–906 (2001).
Adams, R. H. et al. 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 (1999).
Wang, H. U., Chen, Z. F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor Eph-B4. Cell 93, 741–753 (1998).
Gerety, S. S., Wang, H. U., Chen, Z. F. & Anderson, D. J. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol. Cell 4, 403–414 (1999).
Nikolova, Z., Djonov, V., Zuercher, G., Andres, A. C. & Ziemiecki, A. Cell-type specific and estrogen dependent expression of the receptor tyrosine kinase EphB4 and its ligand ephrin-B2 during mammary gland morphogenesis. J. Cell Sci. 111, 2741–2751 (1998).
Gale, N. W. et al. 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 (2001).
Ogawa, K. et al. The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene 19, 6043–6052 (2000).
Simons, K. & Toomre, D. Lipid rafts and signal transduction. Nature Rev. Mol. Cell Biol. 1, 31–39 (2000).
Harris, K. M. Structure, development, and plasticity of dendritic spines. Curr. Opin. Neurobiol. 9, 343–348 (1999).
Segal, M. & Andersen, P. Dendritic spines shaped by synaptic activity. Curr. Opin. Neurobiol. 10, 582–586 (2000).
Bliss, T. V. & Lomo, T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J. Physiol. 232, 331–356 (1973).
Stein, E., Huynh-Do, U., Lane, A. A., Cerretti, D. P. & Daniel, T. O. Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-Jun kinase. J. Biol. Chem. 273, 1303–1308 (1998).
Holland, S. J. et al. Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. EMBO J. 16, 3877–3888 (1997).
Hock, B. et al. PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras-binding protein AF6 depends on the kinase activity of the receptor. Proc. Natl Acad. Sci. USA 95, 9779–9784 (1998).
Ellis, C. et al. A juxtamembrane autophosphorylation site in the Eph family receptor tyrosine kinase, Sek, mediates high affinity interaction with p59fyn. Oncogene 12, 1727–1736 (1996).
Pandey, A., Duan, H. & Dixit, V. M. Characterization of a novel Src-like adapter protein that associates with the Eck receptor tyrosine kinase. J. Biol. Chem. 270, 19201–19204 (1995).
Pandey, A., Lazar, D. F., Saltiel, A. R. & Dixit, V. M. Activation of the Eck receptor protein tyrosine kinase stimulates phosphatidylinositol 3-kinase activity. J. Biol. Chem. 269, 30154–30157 (1994).
Stein, E., Cerretti, D. P. & Daniel, T. O. Ligand activation of ELK receptor tyrosine kinase promotes its association with Grb10 and Grb2 in vascular endothelial cells. J. Biol. Chem. 271, 23588–23593 (1996).
Dodelet, V. C., Pazzagli, C., Zisch, A. H., Hauser, C. A. & Pasquale, E. B. A novel signaling intermediate, SHEP1, directly couples Eph receptors to R-Ras and Rap1A. J. Biol. Chem. 274, 31941–31946 (1999).
Hock, B. et al. Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi-docking site for SH2-domain mediated interactions. Oncogene 17, 255–260 (1998).
Buchert, M. et al. The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialized sites of cell–cell contact in the brain. J. Cell Biol. 144, 361–371 (1999).
Himanen, J. P. et al. Crystal structure of an Eph receptor–ephrin complex. Nature 414, 933–938 (2001).
Himanen, J. P., Henkemeyer, M. & Nikolov, D. B. Crystal structure of the ligand-binding domain of the receptor tyrosine kinase EphB2. Nature 396, 486–491 (1998).
Labrador, J. P., Brambilla, R. & Klein, R. The N-terminal globular domain of Eph receptors is sufficient for ligand binding and receptor signalling. EMBO J. 16, 3889–3897 (1997).