NGF ligand alters NGF signaling via p75(NTR) and trkA.
Nerve growth factor (NGF) binds to two neurotrophin receptors: p75(NTR) and p140(Trk) (TrkA). Both receptors dimerize in response to NGF binding. TrkA homodimers and heteromers of TrkA and p75(NTR) promote cell survival whereas homodimers of p75(NTR) 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 p75(NTR) 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 p75(NTR) and in rat PC12 cells that express both p75(NTR) 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 p75(NTR) 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.
Niederhauser
O
O
Central Nervous System Diseases, F. Hoffmann-LaRoche AG, Pharma Research Basel, Basel, Switzerland.
Mangold
M
M
Schubenel
R
R
Kusznir
E A
EA
Schmidt
D
D
Hertel
C
C
D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005415:Flavins; D006801:Humans; D008024:Ligands; D020932:Nerve Growth Factor / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D016501:Neurites / Q000502:physiology; D016716:PC12 Cells; D010766:Phosphorylation; D011487:Protein Conformation; D011621:Pteridines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism / Q000502:physiology*; D020917:Receptor, trkA / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
C412503:2,3,4,10-tetrahydro-7,10-dimethyl-2,4-dioxobenzo(g)pteridine; D005415:Flavins; D008024:Ligands; D011621:Pteridines; D020800:Receptor, Nerve Growth Factor; D014443:Tyrosine; D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase; D020917:Receptor, trkA