Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses

Stein, Elke; Lane, Andrew A.; Cerretti, Douglas Pat; Schoecklmann, Harald; Schroff, Alfred D.; Etten, Robert L. Van; Daniel, Thomas O.

doi:10.1101/gad.12.5.667

Cited by 398 publications

(343 citation statements)

References 42 publications

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“…For instance, dephosphorylation at Tyr-838 by yet unknown tyrosine phosphatase would lead to an inactive state of the kinase domain, thereby turning o the signal transduction. Interestingly, it was reported that EphB1 receptor complexes recruit low molecular weight phosphotyrosine phosphatase (LMW-PTP) upon treatment with multimeric ligands (Stein et al, 1998a). It will be interesting to examine whether LMW-PTP is able to eliminate phosphorylation at Tyr-838 in EphA8.…”

Section: Discussionmentioning

confidence: 99%

“…Eph-related receptors have been classi®ed into two subfamilies, EphA and EphB, depending on their preferential binding to either glycosylphosphatidylinositol (GPI)-anchored ephrin-A ligands or transmembrane ephrin-B ligands. Since ephrins are membrane-bound proteins that appear to require multimerization for full activity (Davis et al, 1994;Stein et al, 1998a), Eph-ephrin interactions are likely to mediate cell-cell signaling events.…”

Section: Introductionmentioning

confidence: 99%

“…Abnormalities in the formation of brain commissures have been observed in mice lacking EphB2, EphB3 and EphA8 receptors Orioli et al, 1996;Park et al, 1997). Although these studies suggest a major function of Eph receptors and their ligands in the neural patterning of the vertebrate nervous system, Eph and ephrin function is also implicated in angiogenesis and vascular network assembly (Pandey et al, 1995b;Stein et al, 1998a;Wang et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Phosphorylated Tyr-929, in the carboxyterminal tail of EphB1, has been shown to associate with the SH2 domain adapter protein Grb10 (Stein et al, 1996). Interestingly, the equivalent Tyr-929 in EphB1 was required for the recruitment of low molecular weight protein tyrosine phosphatase (LMW-PTP) to receptor complexes upon treatment of multimeric ephrin ligands (Stein et al, 1998a). Although the interacting tyrosine sites in Eph receptors have not been de®ned yet, Grb2, SLAP, and the regulatory subunit p85 of PI-3 kinase were also implicated as immediate downstream targets for Eph receptors (Pandey et al, 1994(Pandey et al, , 1995aStein et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity

Choi

Park

1999

Oncogene

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Eph-related receptors and their ephrin ligands are highly conserved protein families which play important roles in targeting axons and migrating cells. In this study we have examined the functional roles of two major autophosphorylation sites, Tyr-615 and Tyr-838, in the EphA8 receptor. Two-dimensional phosphopeptide mapping analysis demonstrated that Tyr-615 and Tyr-838 constitute major autophosphorylation sites in EphA8. Tyr-615 was phosphorylated to the highest stoichiometry, suggesting that phosphorylation at this site may have a physiologically important role. Upon conservative mutation of Tyr-838 located in the tyrosine kinase domain, the catalytic activity of EphA8 was strikingly reduced both in vitro and in vivo, whereas a mutation at Tyr-615 in the juxtamembrane domain did not impair the tyrosine kinase activity. In vitro binding experiments revealed that phosphorylation at Tyr-615 in EphA8 mediates the preferential binding to Fyn-SH2 domain rather than Src and Ras GTPase-activating protein (Ras GAP)-SH2 domains. Additionally, a high level of EphA8 was detected in Fyn immunoprecipitates in intact cells, indicating that EphA8 and Fyn can physically associate in vivo. In contrast, the association of full-length Fyn to EphA8 containing mutation at either Tyr-615 or Tyr-838 was greatly reduced. These data indicate that phosphorylation of Tyr-615 is critical for determining the association with Fyn whereas the integrity of Tyr-838 phosphorylation is required for e cient phosphorylation at Tyr-615 as well as other major sites. Finally, it was observed that cell attachment responses are attenuated by overexpression of wild type EphA8 receptor but to much less extent by EphA8 mutants lacking phosphorylation at either Tyr-615 or Tyr-838. Furthermore, transient expression of kinase-inactive Fyn in EphA8-overexpressing cells blocked cell attachment responses attenuated by the EphA8 signaling. We therefore propose that Fyn kinase is one of the major downstream targets for the EphA8 signaling pathway leading to a modi®cation of cell adhesion, and that autophosphorylation at Tyr-838 is critical for positively regulating the EphA8 signaling event.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity

Choi

Park

1999

Oncogene

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“…The membrane-bound ephrin ligands require cell-cell contact and multimeric engagement for full signaling activity (Davis et al, 1994;Stein et al, 1998;Egea et al, 2005). The final vascular response to ephrinB2 engagement with its receptors on adjacent cells is shaped by bidirectional signaling interactions within endothelial populations and between endothelial cells and adjacent nonendothelial populations (Heroult et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

Wilkinson

Schittny

Reinhardt

et al. 2008

Developmental Dynamics

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Alveoli are formed in the lung by the insertion of secondary tissue folds, termed septa, which are subsequently remodeled to form the mature alveolar wall. Secondary septation requires interplay between three cell types: endothelial cells forming capillaries, contractile interstitial myofibroblasts, and epithelial cells. Here, we report that postnatal lung alveolization critically requires ephrinB2, a ligand for Eph receptor tyrosine kinases expressed by the microvasculature. Mice homozygous for the hypomorphic knockin allele ephrinB2 ⌬V/⌬V , encoding mutant ephrinB2 with a disrupted C-terminal PDZ interaction motif, show severe postnatal lung defects including an almost complete absence of lung alveoli and abnormal and disorganized elastic matrix. Lung alveolar formation is not sensitive to loss of ephrinB2 cytoplasmic tyrosine phosphorylation sites. Postnatal day 1 mutant lungs show extracellular matrix alterations without differences in proportions of major distal cell populations. We conclude that lung alveolar formation relies on endothelial ephrinB2 function. Developmental Dynamics 237:2220 -2234, 2008.

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Comparative analysis of embryonic gene expression defines potential interaction sites forXenopus EphB4 receptors with ephrin-B ligands

Helbling¹,

Saulnier²,

Robinson³

et al. 1999

Dev. Dyn.

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The Eph family of receptor tyrosine kinases and their ligands, the ephrins, act as signaling molecules regulating the migratory behavior of neurons and neural crest cells, and are implicated in tissue patterning, blood vessel formation, and tumorigenesis. On the basis of structural similarities and overlapping binding specificities, Eph receptors as well as their ligands can be divided into A and B subfamilies with orthologues found in all vertebrates. We describe here the isolation of cDNAs encoding Xenopus EphB4 receptors and show that embryonic expression is prominently associated with the developing vasculature, newly forming somites, the visceral arches, and non‐neuronal tissues of the embryonic head. In a screen to identify potential ligands for EphB4 in Xenopus embryos, we isolated cDNAs for the Xenopus ephrin‐B2 and ‐B3, which demonstrates that the Xenopus genome harbors genes encoding orthologues to all three currently known mammalian ephrin‐B genes. We next performed in situ hybridizations to identify tissues and organs where EphB4 receptors may encounter ephrin‐B ligands during embryonic development. Our analysis revealed distinct, but overlapping patterns of ephrin‐B gene expression. Interestingly, each ephrin‐B ligand displayed expression domains either adjacent to or within EphB4‐expressing tissues. These findings indicate that EphB4 receptors may interact in vivo with multiple B‐class ephrins. The expression patterns also suggest that EphB4 receptors and their ligands may be involved in visceral arch formation, somitogenesis, and blood vessel development. Dev Dyn 1999;216:361–373. ©1999 Wiley‐Liss, Inc.

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Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses

Abstract: Eph family receptor tyrosine kinases (including EphA3,Eph family receptor tyrosine kinases have drawn increasing attention as signaling molecules that direct the targeting behavior of migratory neurons during development, vascular cell assembly, and angiogenesis (Cheng et

Cited by 398 publications

References 42 publications

Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity

Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity

Role for ephrinB2 in postnatal lung alveolar development and elastic matrix integrity

Comparative analysis of embryonic gene expression defines potential interaction sites forXenopus EphB4 receptors with ephrin-B ligands

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