Surfaceome Profiling Reveals Regulators of Neural Stem Cell Function

DeVeale, Brian; Bausch-Fluck, Damaris; Seaberg, Raewyn M.; Runciman, Susan; Akbarian, Vahe; Karpowicz, Phillip; Yoon, Charles; Song, Hannah; Leeder, Rachel; Zandstra, Peter W.; Wollscheid, Bernd; Kooy, Derek van der

doi:10.1002/stem.1550

Cited by 23 publications

(26 citation statements)

References 49 publications

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“…Supporting a role for EphA4-ephrin interaction in axon guidance and inhibition of nerve regeneration after injury, KYL and very recently APY-βAla8.am were shown to inhibit EphA4-dependent growth cone collapse in retinal explants and/or cultures of cortical neurons [31, 65, 66]. Furthermore, inhibition of colony formation and increased cell death in neural stem cell cultures treated with KYL contributed to implicate ephrin-induced EphA4 signaling in the viability of different types of neural stem cells [67]. …”

Section: Peptides Modulating Eph Receptor Function For Research and Tmentioning

confidence: 99%

Targeting the Eph System with Peptides and Peptide Conjugates

Riedl¹,

Pasquale

2015

CDT

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Eph receptor tyrosine kinases and ephrin ligands constitute an important cell communication system that controls development, tissue homeostasis and many pathological processes. Various Eph receptors/ephrins are present in essentially all cell types and their expression is often dysregulated by injury and disease. Thus, the 14 Eph receptors are attracting increasing attention as a major class of potential drug targets. In particular, agents that bind to the extracellular ephrin-binding pocket of these receptors show promise for medical applications. This pocket comprises a broad and shallow groove surrounded by several flexible loops, which makes peptides particularly suitable to target it with high affinity and selectivity. Accordingly, a number of peptides that bind to Eph receptors with micromolar affinity have been identified using phage display and other approaches. These peptides are generally antagonists that inhibit ephrin binding and Eph receptor/ephrin signaling, but some are agonists mimicking ephrin-induced Eph receptor activation. Importantly, some of the peptides are exquisitely selective for single Eph receptors. Most identified peptides are linear, but recently the considerable advantages of cyclic scaffolds have been recognized, particularly in light of potential optimization towards drug leads. To date, peptide improvements have yielded derivatives with low nanomolar Eph receptor binding affinity, high resistance to plasma proteases and/or long in vivo half-life, exemplifying the merits of peptides for Eph receptor targeting. Besides their modulation of Eph receptor/ephrin function, peptides can also serve to deliver conjugated imaging and therapeutic agents or various types of nanoparticles to tumors and other diseased tissues presenting target Eph receptors.

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Section: Peptides Modulating Eph Receptor Function For Research and Tmentioning

confidence: 99%

Targeting the Eph System with Peptides and Peptide Conjugates

Riedl¹,

Pasquale

2015

CDT

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“…A previous mass spectrometry‐based analysis identified novel cell surface markers upregulated on ESC‐derived pNSCs compared to ESCs and dNSCs (DeVeale et al ., ). In this study, C‐Kit and ErbB2 receptors were upregulated on ESC‐derived pNSCs and their inhibition affected pNSC‐derived neurosphere formation from ESCs.…”

Section: Resultsmentioning

confidence: 97%

“…We investigated whether ErbB2 inhibition depleted pup‐derived pNSCs (Fig. A), similar to its effect on ESC‐derived primitive neurospheres (DeVeale et al ., ). At high concentrations (13 μ m ) ErbB2 inhibition completely abolished pNSC‐ and dNSC‐derived neurospheres (data not shown), as previously reported (DeVeale et al ., ).…”

Section: Resultsmentioning

confidence: 99%

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Targeted activation of primitive neural stem cells in the mouse brain

Reeve

Yammine

DeVeale

et al. 2016

Eur J of Neuroscience

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Primitive neural stem cells (pNSCs) are the earliest NSCs to appear in the developing forebrain. They persist into the adult forebrain where they can generate all cells in the neural lineage and therefore hold great potential for brain regeneration. Thus, pNSCs are an ideal population to target to promote endogenous NSC activation. pNSCs can be isolated from the periventricular region as leukaemia inhibitory factor-responsive cells, and comprise a rare population in the adult mouse brain. We hypothesized that the pup periventricular region gives rise to more clonal pNSC-derived neurospheres but that pup-derived pNSCs are otherwise comparable to adult-derived pNSCs, and can be used to identify selective markers and activators of endogenous pNSCs. We tested the self-renewal ability, differentiation capacity and gene expression profile of pup-derived pNSCs and found them each to be comparable to adult-derived pNSCs, including being GFAP(-) , nestin(mid) , Oct4(+) . Next, we used pup pNSCs to test pharmacological compounds to activate pNSCs to promote endogenous brain repair. We hypothesized that pNSCs could be activated by targeting the cell surface proteins C-Kit and ErbB2, which were enriched in pNSCs relative to definitive NSCs (dNSCs) in an in vitro screen. C-Kit and ErbB2 signalling inhibition had distinct effects on pNSCs and dNSCs in vitro, and when infused directly into the adult brain in vivo. Targeted activation of pNSCs with C-Kit and ErbB2 modulation is a valuable strategy to activate the earliest cell in the neural lineage to contribute to endogenous brain regeneration.

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“…For example, EphA4 antagonistic peptides have been studied in neuroprotection and neural repair (Fabes et al, 2007; Galimberti et al, 2010; Murai et al, 2003; Olson et al, 2016). An EphA4-specific peptide (KYL) can regulate the viability of neural stem cells (DeVeale et al, 2014). Since EphA4 has been reported to have a role in Alzheimer’s disease, blocking it by the KYL-peptide can reverse the pathological effects of amyloid-beta oligomers in a cell-based assay for Alzheimer’s (Vargas et al, 2014).…”

Section: Targeting the Eph/ephrin Complex For Drug Developmentmentioning

confidence: 99%

Therapeutic potential of targeting the Eph/ephrin signaling complex

Saha

Robev

Mason

et al. 2018

The International Journal of Biochemistry & Cell Biology

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The Eph-ephrin signaling pathway mediates developmental processes and the proper functioning of the adult human body. This distinctive bidirectional signaling pathway includes a canonical downstream signal cascade inside the Eph-bearing cells, as well as a reverse signaling in the ephrin-bearing cells. The signaling is terminated by ADAM metalloproteinase cleavage, internalization, and degradation of the Eph/ephrin complexes. Consequently, the Eph-ephrin-ADAM signaling cascade has emerged as a key target with immense therapeutic potential particularly in the context of cancer. An interesting twist was brought forth by the emergence of ephrins as the entry receptors for the pathological Henipaviruses, which has spurred new studies to target the viral entry. The availability of high-resolution structures of the multi-modular Eph receptors in complexes with ephrins and other binding partners, such as peptides, small molecule inhibitors and antibodies, offers a wealth of information for the structure-guided development of therapeutic intervention. Furthermore, genomic data mining of Eph mutants involved in cancer provides information for targeted drug development. In this review we summarize the distinct avenues for targeting the Eph-ephrin signaling pathway, including its termination by ADAM proteinases. We highlight the latest developments in Eph-related pharmacology in the context of Eph-ephrin-ADAM-based antibodies and small molecules. Finally, the future prospects of genomics- and proteomics-based medicine are discussed.

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Surfaceome Profiling Reveals Regulators of Neural Stem Cell Function

Cited by 23 publications

References 49 publications

Targeting the Eph System with Peptides and Peptide Conjugates

Targeting the Eph System with Peptides and Peptide Conjugates

Targeted activation of primitive neural stem cells in the mouse brain

Therapeutic potential of targeting the Eph/ephrin signaling complex

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