Nerve growth factor inhibits apoptosis in memory B lymphocytes via inactivation of p38 MAPK, prevention of Bcl-2 phosphorylation, and cytochrome c release

Survival of memory B lymphocytes is tightly linked to the integrity of the Bcl-2 protein and is regulated by a nerve growth factor (NGF) autocrine cir cuit. In factor-starved memory B cells, the addition of exogenous NGF promp tly induced p38 mitogen-activated protein kinase (MAPK), but not c-Jun N-te rminal kinase (JNK), dephosphorylation. Conversely, withdrawal of endogenou s NGF was followed by p38 MAPK activation and translocation onto mitochondr ia, whereby it combined with and phosphorylated Bcl-2, as assessed by co-im munoprecipitation and kinase assays in vivo and in vitro. Mitochondria isol ated from human memory B cells, then exposed to recombinant p38 MAPK, relea sed cytochrome c, as did mitochondria from Bcl-2-negative MDCK cells loaded with recombinant Bcl-2. Apoptosis induced by NGF neutralization could be b locked by the specific p38 MAPK inhibitor SB203580 or by Bcl-2 mutations in Ser-87 or Thr-56. These data demonstrate that the molecular mechanisms und erlying the survival factor function of NGF critically rely upon the contin uous inactivation of p38 MAPK, a Bcl-2-modifying enzyme.