Nerve growth factor-induced protein kinase C stimulation contributes to TrkA-dependent inhibition of p75 neurotrophin receptor sphingolipid signaling.

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 Cgamma (PLCgamma) 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.

Plo I ，Bono F ，Bezombes C ，Alam A ，Bruno A ，Laurent G ... -  《JOURNAL OF NEUROSCIENCE RESEARCH》

Cotransfection of TrkA and p75(NTR) in neuroblastoma cell line (IMR-32) promotes differentiation and apoptosis of tumor cells.

Chen J ，Zhe X 《CHINESE MEDICAL JOURNAL》

Differential activity of the nerve growth factor (NGF) antagonist PD90780 [7-(benzolylamino)-4,9-dihydro-4-methyl-9-oxo-pyrazolo[5,1-b]quinazoline-2-carboxylic acid] suggests altered NGF-p75NTR interactions in the presence of TrkA.

Colquhoun A ，Lawrance GM ，Shamovsky IL ，Riopelle RJ ，Ross GM ... -  《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》

Nerve growth factor exerts differential effects on the growth of human pancreatic cancer cells.

Zhu ZW ，Friess H ，Wang L ，Bogardus T ，Korc M ，Kleeff J ，Büchler MW ... -  《CLINICAL CANCER RESEARCH》

Nerve growth factor regulates substance P in adult sensory neurons through both TrkA and p75 receptors.

Skoff AM ，Adler JE 《EXPERIMENTAL NEUROLOGY》