Phosphorylation of the common neurotrophin receptor p75 by p38 beta 2 kinase affects NF-kappa B and AP-1 activities

The signaling pathways invoked by ligand binding to the common neurotrophin receptor p75(NTR) are incompletely understood. Using the yeast two-hybrid system, we identified the mitogen-activated protein (MAP) kinase p38 beta2 as a specific interactor with the 5th and 6th alpha helices of the p75(NTR) intracytoplasmic region. The consequences of this interaction were studied , using primary cultures of Schwann cells and the 293T cell line. Phosphory lation of p75(NTR) by p38 beta2 was induced in vitro and in vivo by MAP kin ase kinases (MKK) 6 activation. This pathway demonstrated feedback in that nerve growth factor (NGF) binding increased p38 beta2 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 p75(NTR) increases cell survival in certain circumstances.