NEUROTROPHINS - THE BIOLOGICAL PARADOX OF SURVIVAL FACTORS ELICITING APOPTOSIS

Neurotrophins are target-derived soluble polypeptides required for neu ronal survival. Binding of neurotrophins to Trk receptor tyrosine kina ses initiate signaling cascades that promote cell survival and differe ntiation. All family members bind to another receptor (p75(NTR)), whic h belongs to the tumor necrosis factor superfamily. Hence, nerve growt h factor(NGF) and related trophic factors are unique in that two separ ate receptor types are utilized. Although the biological function of p 75(NTR) has been elusive, it has been suggested to mediate apoptosis o f developing neurons in the absence of irk receptors. This presents a tantalizing paradigm, in which life-death decisions of cells are depen dent upon the expression and action of two different receptors with di stinctive signaling mechanisms. In the presence of TrkA receptors, p75 can participate in the formation of high affinity binding sites and e nhanced NGF responsiveness leading to a survival signal. In the absenc e of TrkA receptors, p75 can generate, in only specific cell populatio ns, a death signal. Here we discuss the unique features and implicatio ns of this unusual signal transduction system.