Nerve Growth Factor-dependent Survival of CESS B Cell Line Is Mediated by Increased Expression and Decreased Degradation of MAPK Phosphatase 1

Abstract

The sIgG ؉ lymphoblastoid B cell line CESS spontaneously produces a high amount of nerve growth factor (NGF) and expresses both high affinity (p140 Trk-A ) and low affinity (p75 NTR ) NGF receptors. Autocrine production of NGF maintains the survival of CESS cells through the continuous deactivation of p38 MAPK, an enzyme able to induce Bcl-2 phosphorylation and subsequent cytochrome c release and caspase activation. In this paper, we show that NGF induces transcriptional activation and synthesis of MAPK phosphatase 1 (MKP-1), a dual specificity phosphatase that dephosphorylates p38 MAPK, thus preventing Bcl-2 phosphorylation. Furthermore, NGF increases MKP-1 protein stability by preventing its degradation through the proteasome pathway. Following NGF stimulation, MKP-1 protein mainly localizes on mitochondria, suggesting an interaction with p38 MAPK in this compartment. Incubation of CESS cells with MKP-1-specific antisense oligonucleotides induces cell death, which was not prevented by exogenous NGF. By contrast, overexpression of native MKP-1, but not of its catalytically impaired form, inhibits apoptosis induced by NGF neutralization in CESS cells. Thus, the molecular mechanisms underlying the survival function of NGF in CESS B cell line predominantly consist in maintaining elevated levels of MKP-1 protein, which controls p38 MAPK activation.

Regulation of Intracellular Trafficking of Huntingtin-Associated Protein-1 Is Critical for TrkA Protein Levels and Neurite Outgrowth

“…3F ). This effect is similar to NGF-induced dephosphorylation of p38 mitogen-activated protein kinase (Torcia et al, 2001;Rosini et al, 2004) and other trafficking proteins such as actin depolymerizing factor (Meberg et al, 1998) and myosin light chain (Fujita et al, 2001). Together, the results demonstrate that HAP1A is phosphorylated in neurons and suggest that the dephosphorylation of HAP1A by NGF relocates it to neurites and their tips.…”

Mitogen-Activated Protein (MAP) Kinase/MAP Kinase Phosphatase Regulation: Roles in Cell Growth, Death, and Cancer

“…Despite this, there is a report of a non-nuclear localization for this protein. Treating a human lymphoblastic cell line with nerve growth factor increases mkp-1 mRNA synthesis and protein stability (up to 6 h) with a corresponding increase in translocation of the MKP-1 protein to the mitochondrial compartment (Rosini et al, 2004). The significance of this finding awaits further validation.…”

Linking JNK Activity to the DNA Damage Response

“…Interestingly, MKP-2 is localized specifically in the nucleus, pinpointing the suggestion that specific nuclear activity of JNK is central in JNK-induced apoptosis. 57 Recently, another study showed that the phosphorylation of H2AX by JNK is a very early event in DNA damage-induced apoptosis. 63 Consistent with the idea that H2AX is a substrate for JNK and that γH2AX is required for apoptosis, the authors also described the JNK-dependent pannuclear phosphorylation of H2AX that is proposed to promote the apoptosis of cells subjected to extensive DNA damage.…”

“…55,56 Among these phosphatases, MAPK phosphatase 1 (MKP-1) is a cytoplasmic protein that was shown to be down-regulated in cells subjected to translation inhibition induced by severe DNA damage. 57,58 The inhibition of MKP-1 translation therefore releases the negative control of JNK and is proposed to drive JNK activation in these conditions.…”