Optimal Nerve Growth Factor Trophic Signals Mediated by Synergy of TrkA and p75 Receptor-Specific Ligands

Maliartchouk, Sergei; Saragovi, H. Uri

doi:10.1523/jneurosci.17-16-06031.1997

Cited by 88 publications

(110 citation statements)

References 39 publications

(30 reference statements)

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“…Thus, the absence of p75 ligand interaction by a TrkA agonist might result in reduced TrkA signaling. A similar mechanism was suggested by the finding that TrkA-directed antibodies achieve only partial NGF responses (55,57). It is also important to note that a given partial agonist can be associated with a wide range of efficacies for different signal transduction and biological end points (58).…”

Section: Figmentioning

confidence: 53%

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Nerve Growth Factor (NGF) Loop 4 Dimeric Mimetics Activate ERK and AKT and Promote NGF-like Neurotrophic Effects

Xie

Tisi

Yeo

et al. 2000

Journal of Biological Chemistry

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Previous work indicating that nerve growth factor (NGF) protein loops 2 and 4 interact with TrkA receptors raise the possibility that small molecule mimetics corresponding to TrkA-interacting domains that have NGF agonist activity can be developed. We applied our previously developed strategy of dimeric peptidomimetics to address the hypothesis that loop 4 small molecule dimeric mimetics would activate TrkA-related signal transduction and mimic NGF neurotrophic effects in a structure-specific manner. A loop 4 cyclized peptide dimer demonstrated NGF-like neurotrophic activity, whereas peptides with scrambled sequence, added or substituted residues, or cyclized in monomeric form were inactive. Activity was blocked by the TrkA inhibitors K252a and AG879 but not by NGF p75 receptor blocking antibody. Dimeric, but not monomeric, peptides partially blocked NGF activity. This profile was consistent with that of a NGF partial agonist. ERK and AKT phosphorylation was stimulated only by biologically active peptides and was blocked by K252a. The ERK inhibitor U0126 blocked the neurite-but not the survival-promoting activity of both NGF and active peptide. These studies support the proof of concept that small molecule NGF loop 4 mimetics can activate NGF signaling pathways and can mimic death-preventing and neurite-promoting effects of NGF. This finding will guide the rational design of NGF single-domain mimetics and contribute to elucidating NGF signal transduction mechanisms.Nerve growth factor (NGF) 1 acts via TrkA and p75 receptors to regulate neuronal survival, promote neurite outgrowth, and up-regulate certain neuronal functions such as mediation of pain and inflammation (1-5). These actions suggest that NGF agonists or antagonists might be useful in regulating these processes (6 -8). Factors limiting therapeutic applications of the NGF protein include restricted penetration of the central nervous system and the poor medicinal properties characteristic of most proteins (9, 10). The development of small molecule mimetics with favorable chemical properties that function as agonists or antagonists that mimic or inhibit NGF functions in the appropriate biological context will be critical in advancing potential in vivo applications of NGF. Moreover, in settings in which NGF might contribute to neuronal death, pain, or inflammatory mechanisms, NGF antagonists may be particularly relevant. Creation of single domain NGF mimetics will also constitute a powerful approach for linking specific NGF domains with specific patterns of intracellular signal transduction.A NGF mimetic (agonist or antagonist) would be expected to contain structural determinants of one or more NGF active sites that interact with NGF receptors. Multiple techniques have been used to deduce which domains of the NGF protein interact with NGF receptors (11). A peptide mapping approach in which synthetic peptides with sequences corresponding to specific NGF regions were tested for their ability to inhibit NGF activity pointed to residues 29 -35 as a key active ...

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Section: Figmentioning

confidence: 53%

“…The NGF two-receptor system raises other potential mechanisms contributing to the partial agonist profile of P92. Several studies suggest that unbound p75 negatively regulates and bound p75 positively regulates TrkA function (54,55,56). Thus, the absence of p75 ligand interaction by a TrkA agonist might result in reduced TrkA signaling.…”

Section: Figmentioning

confidence: 99%

Nerve Growth Factor (NGF) Loop 4 Dimeric Mimetics Activate ERK and AKT and Promote NGF-like Neurotrophic Effects

Xie

Tisi

Yeo

et al. 2000

Journal of Biological Chemistry

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“…Cell Survival Assays-Cell survival was measured by quantitative tetrazolium salt reagent (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Sigma) and optical density readings as described (21). Cells were plated in 96-well plates (BD Biosciences) at ϳ5,000 cells/well in serum-free media (SFM) (PFHM-II; Invitrogen), with 0.2% bovine serum albumin (BSA) (Roche Applied Science).…”

Section: Methodsmentioning

confidence: 99%

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

Ivanisevic

Zheng

Woo

et al. 2007

Journal of Biological Chemistry

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Neurotrophins signal via Trk tyrosine kinase receptors. Nerve growth factor (NGF) is the cognate ligand for TrkA, the brainderived neurotrophic factor for TrkB, and NT-3 for TrkC. NT-3 also binds TrkA as a lower affinity heterologous ligand. Because neurotrophin-3 (NT-3) interactions with TrkA are biologically relevant, we aimed to define the TrkA "hot spot" functional docking sites of NT-3. The Trk extracellular domain consists of two cysteine-rich subdomains (D1 and D3), flanking a leucinerich subdomain (D2), and two immunoglobulin-like subdomains IgC1(D4) and IgC2(D5). Previously, the D5 subdomain was defined as the primary ligand-binding site of neurotrophins for their cognate receptors (e.g. NGF binds and activates through TRKA-D5 hot spots). Here binding studies with truncated and chimeric extracellular subdomains show that TRKA-D5 also includes an NT-3 docking and activation hot spot (site 1), and competition studies show that the NGF and NT-3 hot spots on TRKA-D5 are distinct but partially overlapping. In addition, ligand binding studies provide evidence for an NT-3-binding/allosteric site on TRKA-D4 (site 2). NT-3 docking on sites 1 and/or 2 partially blocks NGF binding. Functional survival studies showed that sites 1 and 2 regulate TrkA activation. NT-3 docking on both sites 1 and 2 affords full agonism, which can be additive with NGF activation of Trk. However, NT-3 docking solely on site 1 is partially agonistic but noncompetitively antagonizes NGF binding and activation of Trk. This study demonstrates that Trk signaling is more complex than previously thought because it involves several receptor subdomains and hot spots.

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“…If selective agonists of TrkA were to be applied before extensive CNS damage (e.g., in MCI), it is conceivable that selective protection of cholinergic forebrain neurons and cognitive improvements could be achieved. Additionally, single or concomitant use of pharmacological modulators of p75 action or potentiators of NGF activity may also prove to be useful (Maliartchouk and Saragovi, 1997;Saragovi and Burgess, 1999;Saragovi and Maliartchouk, 1999).…”

Section: Selective Improvement To Cognition and The Cholinergic Systemmentioning

confidence: 99%

Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

Bruno¹,

Clarke²,

Seltzer³

et al. 2004

J. Neurosci.

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Previously, we developed a proteolytically stable small molecule peptidomimetic termed D3 as a selective ligand of the extracellular domain of the TrkA receptor for the NGF. Ex vivo D3 was defined as a selective, partial TrkA agonist. Here, the in vivo efficacy of D3 as a potential therapeutic for cholinergic neurons was tested in cognitively impaired aged rats, and we compared the consequence of partial TrkA activation (D3) versus full TrkA/p75 activation (NGF). We show that in vivo D3 binds to TrkA receptors and affords a significant and long-lived phenotypic rescue of the cholinergic phenotype both in the cortex and in the nucleus basalis. The cholinergic rescue was selective and correlates with a significant improvement of memory/learning in cognitively impaired aged rats. The effects of the synthetic ligand D3 and the natural ligand NGF were comparable. Small, proteolytically stable ligands with selective agonistic activity at a growth factor receptor may have therapeutic potential for neurodegenerative disorders.

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Optimal Nerve Growth Factor Trophic Signals Mediated by Synergy of TrkA and p75 Receptor-Specific Ligands

Abstract: Nerve growth factor (NGF) receptor-mediated signaling was studied using specific monoclonal antibodies (mAbs)

Cited by 88 publications

References 39 publications

Nerve Growth Factor (NGF) Loop 4 Dimeric Mimetics Activate ERK and AKT and Promote NGF-like Neurotrophic Effects

Nerve Growth Factor (NGF) Loop 4 Dimeric Mimetics Activate ERK and AKT and Promote NGF-like Neurotrophic Effects

TrkA Receptor “Hot Spots” for Binding of NT-3 as a Heterologous Ligand

Long-Lasting Rescue of Age-Associated Deficits in Cognition and the CNS Cholinergic Phenotype by a Partial Agonist Peptidomimetic Ligand of TrkA

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