Neurotrophins use the Erk5 pathway to mediate a retrograde survival response

Growth factors synthesized and released by target tissues promote survival and differentiation of innervating neurons. This retrograde signal begins w hen growth factors bind receptors at nerve terminals. Activated receptors a re then endocytosed and transported through the axon to the cell body. Here we show that the mitogen-activated protein kinase (MAPK) signaling pathway s used by neurotrophins during retrograde signaling differ from those used following direct stimulation of the cell soma. During retrograde signaling, endocytosed neurotrophin receptors (Trks) activate the extracellular signa l-related protein kinase S (Erk5) pathway, leading to nuclear translocation of Erk5, phosphorylation of CREB, and enhanced neuronal survival. In contr ast, Erk1/2, which mediates nuclear responses following direct cell body st imulation, does not transmit a retrograde signal. Thus, the Erk5 pathway ha s a unique function in retrograde signaling. Differential activation of dis tinct MAPK pathways may enable an individual growth factor to relay informa tion that specifies the location and the nature of stimulation.