The signaling pathways invoked by ligand binding to the common neurotrophin receptor p75NTR are incompletely understood. Using the yeast two-hybrid system, we identified the mitogen-activated protein (MAP) kinase p38beta2 as a specific interactor with the 5th and 6th alpha helices of the p75NTR intracytoplasmic region. The consequences of this interaction were studied, using primary cultures of Schwann cells and the 293T cell line. Phosphorylation of p75NTR by p38beta2 was induced in vitro and in vivo by MAP kinase kinases (MKK) 6 activation. This pathway demonstrated feedback in that nerve growth factor (NGF) binding increased p38beta2 activity, causing an increase of nuclear factor-kappaB (NF-kappaB) activation and a decrease of AP-1 activation. The mechanisms described explain at least in part why NGF binding to p75NTR increases cell survival in certain circumstances.