Nerve growth factor (NGF) exerts its pro-apoptotic effect via the P75NTR receptor in a cell cycle-dependent manner.
Nerve growth factor (NGF), the prototypic member of the neurotrophin family of growth factors, exerts its action via two receptors, P75NTR and TrkA, the expression of which varies at the cell surface of neuroblastoma cells (SH-SY5Y cells) in a cycle phase-specific manner. NGF was pro-apoptotic on growing cells expressing preferentially P75NTR and exhibited a potent anti-apoptotic effect on quiescent cells, when TrkA was prevalent at the cell surface, showing that NGF can have a dual action on SH-SY5Y cells depending on the relative cell surface expression of TrkA and P75NTR. The pro-apoptotic activity of NGF but not its anti-apoptotic activity was abrogated by an antibody against the extracellular domain of P75NTR and in cell isolated from P75NTR knock-out mice indicating that NGF exhibits a proapoptotic activity via P75NTR exclusively. On the other hand, we showed that the anti-apoptotic activity of NGF was specifically mediated by an interaction with TrkA with no contribution of P75NTR, as demonstrated on SK-N-BE cells transfected with TrkA in which NGF was a potent anti-apoptotic compound but did not exhibit any pro-apoptotic activity. These results support the hypothesis that the survival response to NGF depends on its binding to TrkA without any involvement of P75NTR which in turn selectively mediates the pro-apoptotic activity of NGF with no contribution of TrkA and show that, depending on the growth state of the cells, NGF exhibits dual pro- or anti-apoptotic properties via P75NTR and TrkA, respectively.
Bono
F
F
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Lamarche
I
I
Bornia
J
J
Savi
P
P
Della Valle
G
G
Herbert
J M
JM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D002453:Cell Cycle / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors / Q000378:metabolism* / Q000502:physiology*; D009447:Neuroblastoma / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D020800:Receptor, Nerve Growth Factor; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism* / Q000502:physiology*; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA