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The Journal of Neuroscience, October 15, 2000, 20(20):7556-7563
NF- B Signaling Promotes Both Cell Survival and Neurite Process
Formation in Nerve Growth Factor-Stimulated PC12 Cells
Erik D.
Foehr1, 2,
Xin
Lin1, 2,
Alison
O'Mahony1, 2,
Romas
Geleziunas1, 2,
Ralph A.
Bradshaw3, and
Warner C.
Greene1, 2
1 Gladstone Institute of Virology and Immunology and
2 Departments of Medicine and of Microbiology and
Immunology, University of California, San Francisco, San Francisco,
California 94141-9100, and 3 Departments of Physiology and
Biophysics and of Anatomy and Neurobiology, College of Medicine,
University of California, Irvine, Irvine, California 92697
Nerve growth factor binds to the TrkA and
p75NTR (p75) and generates signals leading to
neuronal cell survival, differentiation, and programmed cell death.
Here we describe a series of experiments involving selective activation
of either TrkA or p75 in which distinct cell-signaling intermediates
promote different cellular consequences. We analyzed pheochromocytoma
12 (PC12) cells stably expressing chimeras consisting of the
extracellular domain of PDGF receptor (PDGFR) fused to the
transmembrane and cytoplasmic segments of p75 or TrkA. Because PC12
cells lack endogenous PDGFR, addition of PDGF to these cell lines
permits selective activation of the p75 or TrkA responses without
stimulating endogenous receptors. Although both p75 and TrkA activated
nuclear factor- B (NF-B), we show that distinct proximal-signaling
intermediates are used by each receptor. A dominant-negative mutant of
TRAF6 blocked p75- but not TrkA-mediated induction of NF-B.
Conversely a dominant-negative mutant of Shc inhibited TrkA but not p75
activation of NF-B. Both of these distinct signaling pathways
subsequently converge, leading to activation of the IB kinase
complex. Moreover, the activation of NF-B by these distinct pathways
after stimulation of either TrkA or p75 leads to different
physiological consequences. Blocking p75-mediated activation of NF-B
by ecdysone-inducible expression of a nondegradable mutant of IB
significantly enhanced apoptosis. In contrast, blocking NF-B
induction via TrkA significantly inhibited neurite process formation in
PC12 cells. Together these findings indicate that, although both of
these receptors lead to the activation of NF-B, they proceed via
distinct proximal-signaling intermediates and contribute to different
cellular outcomes.
Key words:
TrkA; p75; NGF; NF-B; IKK; PC12 cells; apoptosis; neurite process formation
Copyright © 2000 Society for Neuroscience 0270-6474/00/20207556-08$05.00/0
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