The p75 neurotrophin receptor activates Akt (protein kinase B) through a phosphatidylinositol 3-kinase-dependent pathway

The Akt kinase plays a crucial role in supporting Trk-dependent cell surviv al, whereas the p75 neurotrophin receptor (p75NTR) facilitates cellular apo ptosis. The precise mechanism that p75NTR uses to promote cell death is not certain, but one possibility is that p75NTR-dependent ceramide accumulatio n inhibits phosphatidylinositol 3-kinase mediated Akt activation. To test t his hypothesis, we developed a system for examining p75NTR-dependent apopto sis and determined the effect of p75NTR on Akt activation. Surprisingly, p7 5NTR increased, rather than decreased, Akt phosphorylation in a variety of cell types, including human Niemann-Pick fibroblasts, which lack acidic sph ingomyelinase activity. The p75NTR expression level required to elicit Akt phosphorylation was much lower than that required to activate the JNK pathw ay or to mediate apoptosis. Fire show that p75NTR dependent Akt phosphoryla tion was independent of TrkA signaling, required active phosphatidylinosito l 3-kinase, and was associated with increased tyrosine phosphorylation of p 85 and She and with reduced cytosolic tyrosine phosphatase activity. Finall y, we show that p75NTR expression increased sur vival in cells exposed to s taurosporine or subjected to serum withdrawal. These findings indicate that p75NTR facilitates cell survival through novel signaling cascades that res ult in Akt activation.