NGF ligand alters NGF signaling via p75NTR and TrkA

Abstract

Nerve growth factor (NGF) binds to two neurotrophin receptors: p75NTR and p140Trk (TrkA). Both receptors dimerize in response to NGF binding. TrkA homodimers and heteromers of TrkA and p75NTR promote cell survival whereas homodimers of p75NTR mediate apoptosis upon binding of NGF. The interaction between receptor and NGF can be inhibited either on the level of the ligand by altering NGF conformation so that NGF is no longer recognized by the receptor or on the level of the receptor by blocking the binding site of p75NTR or TrkA. The effect of altering NGF conformation on NGF signaling was investigated in two neuron‐like cell lines: in human SK‐N‐MC cells that express only p75NTR and in rat PC12 cells that express both p75NTR and TrkA. In the present study we demonstrate that Ro 08‐2750 binds to the NGF dimer thereby probably inducing a change in its conformation such that NGF cannot bind to p75NTR anymore. In SK‐N‐MC cells this leads to inhibition of NGF‐induced programmed cell death. In PC12 cells enhanced signaling through TrkA was observed. J. Neurosci. Res. 61:263–272, 2000. © 2000 Wiley‐Liss, Inc.

Amyloid β Binds Trimers as Well as Monomers of the 75-kDa Neurotrophin Receptor and Activates Receptor Signaling

“…Cell Culture-p75 NTR -, pCMV-, and p140 trkA -NIH 3T3 cells (kindly provided by Dr. M. V. Chao, New York University Medical Center, New York, NY) and E17 fetal rat cortical neurons were generated and maintained as described (5). Briefly, NIH 3T3 cells were maintained in DMEM supplemented with 10% fetal bovine serum in the presence of penicillin (45 ng/ml), streptomycin (68 ng/ml), and hygromycin B (17.5 ng/ml).…”

Multipotent Neurotrophin Antagonist Targets Brain-Derived Neurotrophic Factor and Nerve Growth Factor

“…1, a and b). By use of a structural similarity search based on known NGF antagonists [ALE-0540 (Owolabi et al, 1999); Ro 08-2750 (Niederhauser et al, 2000), and PD 90780 (Colquhoun et al, 2004)], a combinatorial panel of furan-ring derivatives was identified and screened in silico. Flexible docking experiments identified compound Y1036 (Fig.…”

“…For example, ALE-0540 interacts with NGF inhibiting binding to trkA or p75 NTR (Owolabi et al, 1999). Ro 08-2750 is also an effective NGF-binding agent and prevents NGF from interacting with either receptor, but higher concentrations are required to affect trkA (Niederhauser et al, 2000). PD90780 also binds NGF, but it is more effective at blocking NGF/p75 NTR interaction than NGF/trkA (Spiegel et al, 1995;Colquhoun et al, 2004).…”

“…Analytical ultracentrifugation was performed by use of a Beckman XL-A according to Niederhauser et al (2000). Equimolar concentration of recombinant BDNF (Peprotech; Rocky Hill, NJ), NGF (Serotec, Raleigh, NC), or lysozyme control (Sigma-Aldrich, St. Louis, MO) was incubated with 20 M Y1036 for 1 h at 25°C in 10 mM Tris-HCl buffer, pH 7.3.…”

Differential Activity of the Nerve Growth Factor (NGF) Antagonist PD90780 [7-(Benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic Acid] Suggests Altered NGF-p75NTRInteractions in the Presence of TrkA

“…In a recent study, the presence and combination of receptor types expressed on different cell lines affected the ability of a NGF antagonist, Ro 08-2780, to modify the pro-apoptotic and prosurvival actions of nerve (Niederhauser et al, 2000). The antagonist ALE-0540 prevented NGF binding to both p75 NTR and TrkA receptors (Owolabi et al, 1999) and was used in the same study to examine and outline a role for NGF in persistent pain states.…”