Nerve growth factor (NGF) has been implicated as both an inhibitor and an inducer of apoptosis. Binding of NGF to its TrkA receptor is generally considered to have an antiapoptotic effect. However, neuroblastomas that overexpress TrkA have a good prognosis and frequently regress by apoptosis either spontaneously or after chemotherapeutic treatment, whereas those that express little or no TrkA are lethal in 80-95% of patients, despite maximal therapy. We now report that NGF treatment of PC12 neural crest tumor cells trkA-transfected to express TrkA at levels analogous to those seen in "good prognosis" neuroblastomas results in cell death; similar treatment of native cells that express TrkA at levels similar to those of "poor prognosis" neuroblastomas has no effect on cell survival. Morphological and biochemical studies indicate that NGF induces atypical apoptosis that is abrogated by the tyrosine kinase inhibitor K252alpha, but not by an inhibitor of NGF-p75 binding, in trkA-transfected PC12 cells. Differential activation of the TrkA-phosphorylated mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase 1-phosphorylated ERK-phosphorylated cAMP-responsive element-binding protein and TrkA-phosphorylated MAP/ERK kinase 3/6-phosphorylated p38 MAP signal transduction pathways, also suppressible by K252alpha, occurs in the two cell types. This difference may mediate their differential survival after exposure to NGF.