Neurotrophin receptors: mediators of life and death

Chao, Moses V.; Casaccia‐Bonnefil, Patrizia; Carter, Bruce; Chittka, Alexandra; Kong, Hyesik; Yoon, Sung Ok

doi:10.1016/s0165-0173(97)00036-2

Cited by 146 publications

(33 citation statements)

References 37 publications

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“…P92 promoted both survival and neurite outgrowth, whereas P7 primarily promoted survival rather than neurite outgrowth. This distinction in biological activity profile is consistent with studies demonstrating that TrkA regulates both survival and neurite outgrowth, whereas p75 primarily regulates cell death (3,4,17,29). These distinct profiles in TrkA versus p75 mediation and resulting biological activity by the P92 and P7 peptidomimetics indicate that it may be possible to design small molecule NGF mimetics acting via partly non-overlapping signaling networks to promote (or prevent) different sets of biological end points.…”

Section: Figsupporting

confidence: 84%

“…The NGF sites interacting with TrkA have also been derived via chemical modification (11,19,20), recombinant protein (18, 20 -23), and NGF-TrkA co-crystallization approaches (24). Taken together, these studies indicate that TrkA binding sites consist of residues in NGF loop 2 (residues 40 -49), loop 4 (residues 91-97), the N terminus (residues [1][2][3][4][5][6][7][8], and the C terminus (residues 111-115).…”

mentioning

confidence: 99%

“…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)(2)(3)(4)(5). These actions suggest that NGF agonists or antagonists might be useful in regulating these processes (6 -8).…”

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confidence: 99%

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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: Figsupporting

confidence: 84%

mentioning

confidence: 99%

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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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“…The p75 receptor is a member of the TNF receptor superfamily (Bredesen and Rabizadeh, 1997;Chao et al, 1998b).…”

Section: Introductionmentioning

confidence: 99%

“…As a clear example, the Trks (Yamashiro et al, 1996;Brodeur et al, 1997;Kramer et al, 1997) and the p75 receptors (Frade and Barde, 1998) can either rescue cells from apoptosis or lead to apoptosis; these effects can be ligand-dependent or -independent (Bredesen and Rabizadeh, 1997;Chao et al, 1998a); and may depend on cell cycle (Urdiales et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Differential cross-regulation of TrkA and TrkC tyrosine kinase receptors with p75

2003

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The neurotrophins neurotrophin-3 (NT-3), brain-derived growth factor (BDNF) and nerve growth factor (NGF) bind to the p75 receptor, but each neurotrophin also binds a more selective Trk receptor (e.g. TrkA-NGF and TrkC-NT-3). The biochemical signals following engagement of either Trk or p75 with ligands are well understood, but long-term biological outcomes (trophic, proapoptotic or differentiative) remain unclear because they are cell/tissue specific. For example, Trk receptors are usually trophic but when overexpressed they can be proapoptotic in neuroblastomas and medulloblastomas. We hypothesized that coexpression of Trk and p75 receptors may lead to cross-regulation of signals and different biological outcomes; and used receptor-selective ligands to study crossregulation by these receptors. We show that in the absence of Trk activation, expression of TrkC is permissive of p75 trophic and differentiation signals induced by p75 ligands, whereas expression of TrkA abolishes trophic and differentiation signals induced by p75 ligands. In contrast, in the presence of Trk activation, p75 ligands can regulate TrkA-mediated survival and TrkC-mediated differentiation. Therefore, a complex homeostasis of p75-selective and Trk-selective signals may determine the fate of cells expressing both receptors.

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