Molecular cloning of a ligand for the EPH-related receptor protein-tyrosine kinase Htk.

Bennett, Brian D.; Zeigler, Francis C.; Gu, Qimin; Fendly, Brian M.; Goddard, Audrey D.; Gillett, Nancy A.; Matthews, William

doi:10.1073/pnas.92.6.1866

Cited by 99 publications

(64 citation statements)

References 24 publications

(34 reference statements)

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“…The ligands of the ephrin-A subfamily are anchored by a glycosyl phosphatidylinositol (GPI) lipid tail, and are represented by ®ve known ligands. The ephrin-B ligands are anchored by a transmembrane domain and in addition to ephrin-B3, described here, include two other ligands, ephrin-B1 (originally named LERK-2/Elk-L/Cek5-L) (Beckmann et al, 1994;Davis et al, 1994;Shao et al, 1994) and ephrin-B2 (originally named ELF-2/Htk-L) (Bennett et al, 1995;Bergemann et al, 1995). Recent evidence indicates that receptorligand binding can result in phosphorylation of the transmembrane ligands, indicating bi-directional signal transduction through both the receptor and the ligand (Bruckner et al, 1997;Holland et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

et al. 1998

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The ephrins are a family of ligands that bind to Eph family receptor tyrosine kinases, and have been implicated in axon guidance and other patterning processes during vertebrate development. We describe here the identi®cation and characterization of murine ephrin-B3. The cDNA encodes a 340 amino acid transmembrane molecule, most closely related to the two other known transmembrane ligands, ephrin-B1 and ephrin-B2. In addition to homology in their extracellular receptor binding domains, these transmembrane ligands share striking homology between their cytoplasmic domains, with 31 of the last 34 amino acids of ephrin-B3 being identical to ephrin-B2, suggesting functional interactions of the cytoplasmic tail. While most Eph family ligands are promiscuous in their interactions with Eph receptors, binding studies with the ®ve receptors known to bind other transmembrane ligands only revealed a high a nity interaction of ephrin-B3 with EphB3, with a dissociation constant of approximately 1 nM. In situ hybridization of mouse embryos showed ephrin-B3 is expressed prominently at the dorsal and ventral midline of the neural tube, particularly in the¯oor plate, a structure with key functions in patterning the nervous system. The isolation of this ligand may help to elucidate the molecular basis of patterning activities at the neural tube midline.

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Section: Introductionmentioning

confidence: 99%

Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

et al. 1998

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“…Based upon their binding a nity, the GPI-linked ligands have been placed in a subgroup having greater a nity for Eck-related receptors, while transmembrane ligands preferentially bind the Elkrelated receptors (Gale et al, 1996a). Lerk2 (Cek5-L), HTK-L (Elf-2) and Elk-L3 are type I transmembrane proteins which share very highly conserved C-terminal domains (Beckmann et al, 1994;Bennett et al, 1995;Bergemann et al, 1995;Gale et al, 1996b;Shao et al, 1994). While membrane anchorage has been shown to be necessary for the activation of receptors by these ligands Bergemann et al, 1995;Brambilla et al, 1995;Davis et al, 1994;Shao et al, 1994Shao et al, , 1995, a soluble form of Lerk-2 ligand has been reported to stimulate autophosphorylation activity of the Hek-2 receptor (Bohme et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Identification of XLerk, an Eph family ligand regulated during mesoderm induction and neurogenesis in Xenopus laevis

et al. 1997

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“…This supports the idea that most of the peptides that we have identified mimic the G-H loop of the ephrins, albeit through different mechanisms. Finally, instead of the proline found in most other peptides, three of the EphB4-binding peptides contain a tryptophan, which is conserved in the G-H loop of the preferred ligand for EphB4, ephrin-B2 (38).…”

Section: Fig 5 Peptides As Ephb Receptor-targeting Agentsmentioning

confidence: 99%

EphB Receptor-binding Peptides Identified by Phage Display Enable Design of an Antagonist with Ephrin-like Affinity

Koolpe

Burgess

Dail

et al. 2005

Journal of Biological Chemistry

131

157

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The Eph receptor tyrosine kinases are overexpressed in many pathologic tissues and have therefore emerged as promising drug target candidates. However, there are few molecules available that can selectively bind to a single Eph receptor and not other members of this large receptor family. Here we report the identification by phage display of peptides that bind selectively to different receptors of the EphB class, including EphB1, EphB2, and EphB4. Peptides with the same EphB receptor specificity compete with each other for binding, suggesting that they have partially overlapping binding sites. In addition, several of the peptides contain amino acid motifs found in the G-H loop of the ephrin-B ligands, which is the region that mediates high-affinity interaction with the EphB receptors. Consistent with targeting the ephrin-binding site, the higher affinity peptides antagonize ephrin binding to the EphB receptors. We also designed an optimized EphB4-binding peptide with affinity comparable with that of the natural ligand, ephrin-B2. These peptides should be useful as selective inhibitors of the pathological activities of EphB receptors and as targeting agents for imaging probes and therapeutic drugs.

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Molecular cloning of a ligand for the EPH-related receptor protein-tyrosine kinase Htk.

Abstract: Htk is a receptor protein-tyrosine kinase that is related to the EPH subfamily of tyrosine kinases.

Cited by 99 publications

References 24 publications

Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

Ephrin-B3, a ligand for the receptor EphB3, expressed at the midline of the developing neural tube

Identification of XLerk, an Eph family ligand regulated during mesoderm induction and neurogenesis in Xenopus laevis

EphB Receptor-binding Peptides Identified by Phage Display Enable Design of an Antagonist with Ephrin-like Affinity

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