Distinct Neurite Outgrowth Signaling Pathways Converge on ERK Activation

Perron, Jeanette C.; Bixby, John L.

doi:10.1006/mcne.1999.0753

Cited by 157 publications

(113 citation statements)

References 70 publications

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“…Similarly, U0126 had no effect on cell survival supported by P92, with survival in the presence of U0126 at 104% that measured without U0126. These findings are consistent with previous studies demonstrating that inhibition of growth factor-induced ERK pathway signaling results in a loss of neurite outgrowth without affecting cell survival (50,51). The matching profile of the inhibitory effects of U126 on NGF and P92 further support the hypothesis that P92 acts in part via NGF-like activation of ERK signal transduction.…”

Section: Fig 5 P92 Activates Erk Tyrosine Phosphorylationsupporting

confidence: 92%

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: Fig 5 P92 Activates Erk Tyrosine Phosphorylationsupporting

confidence: 92%

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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“…To examine directly the role of MAP kinase signaling in the regulation of L1-CAM function in situ, we cultured cerebellar granular neurons on substrates coated with the L1-CAM ligand Ng-CAM, a chick L1-CAM homolog. As MAP kinase pathway inhibitors block neuronal growth through both L1-CAM and other receptor families, MAP kinase activity has been suggested to regulate pathways common to nerve growth in general (Perron and Bixby, 1999;Schmid et al, 2000). To determine if L1-CAM function was itself modulated by MAP kinase activity, we grew neurons in the presence of both a MEK inhibitor (U0126) and a peptide AP-YF that inhibits L1-CAM interactions with ankyrin.…”

Section: The Map Kinase Pathway Regulates L1-cam-mediated Neuronal Grmentioning

confidence: 99%

MAP Kinase Pathway–dependent Phosphorylation of the L1-CAM Ankyrin Binding Site Regulates Neuronal Growth

Whittard

Sakurai

Cassella

et al. 2006

MBoC

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The growth of neuronal processes depends critically on the function of adhesion proteins that link extracellular ligands to the cytoskeleton. The neuronal adhesion protein L1-CAM serves as a receptor for nerve growth-promoting proteins, a process that is inhibited by the interaction between L1-CAM and the cytoskeleton adaptor ankyrin. Using a novel reporter based on intramolecular bioluminescence resonance energy transfer, we have determined that the MAP kinase pathway regulates the phosphorylation of the FIGQY motif in the adhesion protein L1-CAM and its interaction with ankyrin B. MAP kinase pathway inhibitors block L1-CAM-mediated neuronal growth. However, this blockade is partially rescued by inhibitors of L1-CAM-ankyrin binding. These results demonstrate that the MAP kinase pathway regulates L1-CAMmediated nerve growth by modulating ankyrin binding, suggesting that nerve growth can be regulated at the level of individual receptors.

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“…Its action is mediated, downstream of its receptor(s), by different signal transduction pathways, whose differential activation may explain the specificity of action of the factor. The processes in which it has been shown to play a role range from neuronal survival to neurite growth and nerve repair [4,8,13,17,18].…”

Section: Introductionmentioning

confidence: 99%

Calcium signals induced by FGF-2 in parasympathetic neurons: Role of second messenger pathways

Zamburlin¹,

Gilardino²,

Farcito³

et al. 2012

Neuroscience Letters

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Distinct Neurite Outgrowth Signaling Pathways Converge on ERK Activation

Cited by 157 publications

References 70 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

MAP Kinase Pathway–dependent Phosphorylation of the L1-CAM Ankyrin Binding Site Regulates Neuronal Growth

Calcium signals induced by FGF-2 in parasympathetic neurons: Role of second messenger pathways

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