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J. Biol. Chem., Vol. 275, Issue 38, 29868-29874, September 22, 2000
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From the Department of Neurology, Veterans Affairs Medical Center
and University of California, San Francisco, California 94121
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) Loop 4 Dimeric Mimetics Activate
ERK and AKT and Promote NGF-like Neurotrophic Effects*
*
This work was supported by the Alzheimer's Association (to
F. L.), the John Douglas French Foundation (to F. L.), the Veterans Administration (to F. L.), and National Institutes of Health Grant NS37309 (to T. Y.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Neurology,
VAMC/UCSF, 4150 Clement St., San Francisco, CA 94121. Tel.: 415-750-2011; Fax: 415-750-2273; E-mail: LFM@itsa.UCSF.edu.
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