NF-kappa B signaling promotes both cell survival and neurite process formation in nerve growth factor-stimulated PC12 cells

Nerve growth factor binds to the TrkA and p75(NTR) (p75) and generates sign als leading to neuronal cell survival, differentiation, and programmed cell death. Here we describe a series of experiments involving selective activa tion of either TrkA or p75 in which distinct cell-signaling intermediates p romote different cellular consequences. We analyzed pheochromocytoma 12 (PC 12) cells stably expressing chimeras consisting of the extracellular domain of PDGF receptor (PDGFR) fused to the transmembrane and cytoplasmic segmen ts of p75 or TrkA. Because PC12 cells lack endogenous PDGFR, addition of PD GF to these cell lines permits selective activation of the p75 or TrkA resp onses without stimulating endogenous receptors. Although both p75 and TrkA activated nuclear factor-kappa B (NF-kappa B), we show that distinct proxim al-signaling intermediates are used by each receptor. A dominant-negative m utant of TRAF6 blocked p75- but not TrkA-mediated induction of NF-kappa B. Conversely a dominant-negative mutant of Shc inhibited TrkA but not p75 act ivation of NF-kappa B. Both of these distinct signaling pathways subsequent ly converge, leading to activation of the I kappa B kinase complex. Moreove r, the activation of NF-kappa B by these distinct pathways after stimulatio n of either TrkA or p75 leads to different physiological consequences. Bloc king p75- mediated activation of NF-kappa B by ecdysone-inducible expressio n of a nondegradable mutant of I kappa Ba significantly enhanced apoptosis. In contrast, blocking NF-kappa B induction via TrkA significantly inhibite d neurite process formation in PC12 cells. Together these findings indicate that, although both of these receptors lead to the activation of NF-kappa B, they proceed via distinct proximal-signaling intermediates and contribut e to different cellular outcomes.