Eph/ephrin Signaling as a Potential Therapeutic Target After Central Nervous System Injury

Du, Jiulin; Fu, Christine; Sretavan, David W.

doi:10.2174/138161207781368594

Cited by 56 publications

(22 citation statements)

References 107 publications

(126 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Many Eph receptors and ephrins are upregulated after traumatic or ischemic nervous system injury and negatively affect axon sprouting and other repair processes (2; 30). Indeed, a number of studies have linked pharmacological inhibition of EphA4-ephrin binding and EphA4 gene inactivation with improved functional recovery in rodent spinal cord injury models (41–43).…”

Section: Nervous Systemmentioning

confidence: 99%

See 1 more Smart Citation

Eph Receptors and Ephrins: Therapeutic Opportunities

Barquilla

Pasquale

2015

Annu. Rev. Pharmacol. Toxicol.

260

287

View full text Add to dashboard Cite

The Eph receptor tyrosine kinase family plays important roles in developmental processes, adult tissue homeostasis and various diseases. Interaction with ephrin ligands on the surface of neighboring cells triggers Eph receptor kinase-dependent signaling. The ephrins can also transmit signals, leading to bidirectional cell contact-dependent communication. Moreover, Eph receptors and ephrins can function independently of each other, through interplay with other signaling systems. Given their involvement in many pathological conditions ranging from neurological disorders to cancer and viral infections, Eph receptors and ephrins are increasingly recognized as attractive therapeutic targets and a variety of strategies are being explored to modulate their expression and function. Eph receptor/ephrin upregulation in cancer cells, the angiogenic vasculature, and injured or diseased tissues also offers opportunities for Eph/ephrin-based targeted drug delivery and imaging. Thus, despite the challenges presented by the complex biology of the Eph receptor/ephrin system, exciting possibilities exist for therapies exploiting these molecules.

show abstract

Section: Nervous Systemmentioning

confidence: 99%

“…Other recent reviews provide more details on Eph/ephrin signaling mechanisms (1; 4; 8; 9; 13; 17; 28; 29), roles in specific diseases (2; 4; 30–35), targeting agents (4; 36; 37) and related patent applications and clinical trials (38; 39). …”

Section: Introductionmentioning

confidence: 99%

Eph Receptors and Ephrins: Therapeutic Opportunities

Barquilla

Pasquale

2015

Annu. Rev. Pharmacol. Toxicol.

260

287

View full text Add to dashboard Cite

show abstract

“…For example, EphA4 interacts with ephrin-B1 expressed in human platelets to stabilize blood clot formation through an integrin-dependent mechanism [28]. By interacting with ephrin-B2 and/or ephrin-B3, EphA4 regulates neuronal circuits important for coordinated movement and may inhibit the regeneration of injured spinal cord axons [29-31]. As a consequence, EphA4 was also considered as a promising target for the development of small molecule drugs to treat human diseases [14,32].…”

Section: Introductionmentioning

confidence: 99%

Protein dynamics at Eph receptor-ligand interfaces as revealed by crystallography, NMR and MD simulations

2012

View full text Add to dashboard Cite

BackgroundThe role of dynamics in protein functions including signal transduction is just starting to be deciphered. Eph receptors with 16 members divided into A- and B- subclasses are respectively activated by 9 A- and B-ephrin ligands. EphA4 is the only receptor capable of binding to all 9 ephrins and small molecules with overlapped interfaces.ResultsWe first determined the structures of the EphA4 ligand binding domain (LBD) in two crystals of P1 space group. Noticeably, 8 EphA4 molecules were found in one asymmetric unit and consequently from two crystals we obtained 16 structures, which show significant conformational variations over the functionally critical A-C, D-E, G-H and J-K loops. The 16 new structures, together with previous 9 ones, can be categorized into two groups: closed and open forms which resemble the uncomplexed and complexed structures of the EphA4 LBD respectively. To assess whether the conformational diversity over the loops primarily results from the intrinsic dynamics, we initiated 30-ns molecular dynamics (MD) simulations for both closed and open forms. The results indicate that the loops do have much higher intrinsic dynamics, which is further unravelled by NMR H/D exchange experiments. During simulations, the open form has the RMS deviations slightly larger than those of the closed one, suggesting the open form may be less stable in the absence of external contacts. Furthermore, no obvious exchange between two forms is observed within 30 ns, implying that they are dynamically separated.ConclusionsOur study provides the first experimental and computational result revealing that the intrinsic dynamics are most likely underlying the conformational diversity observed for the EphA4 LBD loops mediating the binding affinity and specificity. Interestingly, the open conformation of the EphA4 LBD is slightly unstable in the absence of it natural ligand ephrins, implying that the conformational transition from the closed to open has to be driven by the high-affinity interaction with ephrins because the weak interaction with small molecule was found to be insufficient to trigger the transition. Our results therefore highlight the key role of protein dynamics in Eph-ephrin signalling and would benefit future design of agonists/antagonists targeting Eph receptors.

show abstract

“…For instance, the EphA2 and EphB4 receptors are highly expressed in many types of cancers, where their interaction with ephrin ligands can promote tumor angiogenesis [18–21] and in some cases also cancer cell malignancy [17,18,22]. Activation of members of the EphA receptor class, including EphA4, by ephrin ligands has also been shown to trigger growth cone collapse in vitro and inhibit nerve regeneration after spinal cord injury [17,23–26], suggesting that interfering with EphA4-ephrin interaction may be beneficial for the regrowth of damaged axons [27]. Therefore, inhibiting Eph receptor and ephrin signaling could have a variety of therapeutic applications [18,28].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Eph receptor–ephrin ligand interaction by tea polyphenols

Noberini

Koolpe

Lamberto

et al. 2012

Pharmacological Research

View full text Add to dashboard Cite

Tea contains a variety of bioactive chemicals, such as catechins and other polyphenols. These compounds are thought to be responsible for the health benefits of tea consumption by affecting the function of many cellular targets, not all of which have been identified. In a high-throughput screen for small molecule antagonists of the EphA4 receptor tyrosine kinase, we identified five tea polyphenols that substantially inhibit EphA4 binding to a synthetic peptide ligand. Further characterization of theaflavin monogallates from black tea and epigallocatechin-3,5-digallate from green tea revealed that these compounds at low micromolar concentrations also inhibit binding of the natural ephrin ligands to EphA4 and several other Eph receptors in in vitro assays. The compounds behave as competitive EphA4 antagonists, and their inhibitory activity is affected by amino acid mutations within the ephrin binding pocket of EphA4. In contrast, the major green tea catechin, epigallocatechin-3-gallate (EGCG), does not appear to be an effective Eph receptor antagonist. In cell culture assays, theaflavin monogallates and epigallocatechin-3,5-digallate inhibit ephrin-induced tyrosine phosphorylation (activation) of Eph receptors and endothelial capillary-like tube formation. However, the wider spectrum of Eph receptors affected by the tea derivatives in cells suggests additional mechanisms of inhibition besides interfering with ephrin binding. These results show that tea polyphenols derived from both black and green tea can suppress the biological activities of Eph receptors. Thus, the Eph receptor tyrosine kinase family represents an important class of targets for tea-derived phytochemicals.

show abstract

Eph/ephrin Signaling as a Potential Therapeutic Target After Central Nervous System Injury

Cited by 56 publications

References 107 publications

Eph Receptors and Ephrins: Therapeutic Opportunities

Eph Receptors and Ephrins: Therapeutic Opportunities

Protein dynamics at Eph receptor-ligand interfaces as revealed by crystallography, NMR and MD simulations

Inhibition of Eph receptor–ephrin ligand interaction by tea polyphenols

Contact Info

Product

Resources

About