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The biological activity of proNGF is determined by the relative levels of TrkA and p75NTR receptors
Author(s) -
Fahnestock Margaret,
Ioannou Maria S.,
Masoudi Raheleh
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.1010.6
Subject(s) - low affinity nerve growth factor receptor , tropomyosin receptor kinase a , nerve growth factor , neurotrophin , receptor , neurotrophic factors , microbiology and biotechnology , biology , chemistry , biochemistry
Nerve growth factor (NGF) regulates neuronal survival, differentiation and function and is found in CNS as the NGF precursor, proNGF. Whether proNGF is neurotrophic or apoptotic is controversial. NGF and proNGF bind the TrkA receptor which is responsible for cell survival and differentiation, and p75NTR, which can mediate apoptosis. ProNGF has a higher affinity for p75NTR while NGF has a higher affinity for TrkA. It is known that the ratio of TrkA to p75NTR can determine whether mature NGF signals cell survival or death. We show here that the ratio of TrkA to p75NTR also determines the fate of cells treated with proNGF. We used growth conditions, siRNA and knockouts to modulate TrkA levels in PC12 cells expressing both TrkA and p75NTR. We found that although proNGF is neurotrophic for cells expressing high levels of TrkA and moderate or low levels of p75NTR, proNGF induces apoptosis in cells expressing lower levels of TrkA and higher levels of p75NTR, while NGF is neurotrophic unless TrkA is eliminated. Thus, proNGF is more sensitive to relative TrkA/p75NTR levels than NGF. In conclusion, the biological activity of proNGF can be altered by modulating relative levels of TrkA and p75NTR, suggesting that proNGF is neurotrophic under normal circumstances, but that a shift in the balance between its two receptors, as occurs in neurodegenerative disease or injury, may alter proNGF signaling from cell survival to cell death. Support: Canadian Institutes of Health Research (CIHR) Grants MOP‐64382 and IAO‐94360 to MF, NSERC Scholarship to MSI, Ministry of Science of Iran Scholarship to RM.