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Nerve growth factor‐induced protein kinase C stimulation contributes to TrkA‐dependent inhibition of p75 neurotrophin receptor sphingolipid signaling
Author(s) -
Plo I.,
Bono F.,
Bezombes C.,
Alam A.,
Bruno A.,
Laurent G.
Publication year - 2004
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20189
Subject(s) - tropomyosin receptor kinase a , low affinity nerve growth factor receptor , nerve growth factor , neurotrophin , microbiology and biotechnology , stimulation , signal transduction , receptor , chemistry , neuroscience , biology , biochemistry
Previous studies have established that reciprocal interactions between the low‐affinity p75 nerve growth factor (NGF) receptor (p75 NTR ) and the high‐affinity TrkA NGF receptor can dictate the cellular response to NGF. As the most important interaction, TrkA signaling was found to inhibit p75 NTR ‐mediated sphingomyelinase (SMase) stimulation, ceramide production, and apoptosis. However, the mechanism by which TrkA counteracts p75 NTR ‐coupled sphingolipid signaling is still unclear. Considering the stimulatory effect of NGF on protein kinase C (PKC) activity, we investigated the role of PKC in TrkA/p75 NTR signaling interaction. In this study, we found that, in SK‐N‐BE cells, which selectively express p75 NTR , phorbol ester‐induced PKC stimulation resulted in the abrogation of SMase stimulation and ceramide production induced by NGF. Moreover, in SK‐N‐BE neuroblastoma cells, which selectively express TrkA, NGF stimulated global PKC activity through two independent pathways involving phospholipase Cγ (PLCγ) and phosphoinositide‐3 kinase (PI3K). In SH‐SY5Y, another neuroblastoma cell line, which coexpresses TrkA and p75 NTR , NGF induced PKC stimulation through a TrkA/PI3K signaling pathway, whereas there was no ceramide production. However, in these cells, the inhibition of TrkA, PI3K, and PKC resulted in the restoration of NGF‐induced ceramide production. Thus, our study demonstrates for the first time that TrkA interferes with p75 NTR signaling through a PI3K/PKC‐dependent mechanism. © 2004 Wiley‐Liss, Inc.