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C-Jun N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82.

ABSTRACT: Protein kinases play an important role in the maintenance of homeostasis between cell survival and apoptosis. Deregulation of these kinases leads to various pathological manifestations, such as cancer and neurodegenerative diseases. The MST1 encodes a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn phosphorylates its downstream targets, Histone H2B and FOXO. However, the upstream regulators of MST1 kinase have been poorly studied. In this study, we report that JNK (c-Jun N-terminal kinase) phosphorylates MST1 at serine 82, which leads to the enhancement of MST1 activation. Accordingly, the activation of MST1 phosphorylates FOXO3 at serine 207 and promotes cell death. The inhibition of JNK kinase per se attenuates MST1 activity and nuclear translocation as well as MST1-induced apoptosis. We also find the S82A (serine mutated to alanine) diminishes MST1 activation and its effect on the FOXO transcription activity. Collectively, these findings define the novel feedback regulation of MST1 kinase activation by its putative substrate, JNK, with implication for our understanding of the signaling mechanism during cell death.

SUBMITTER: Bi W

PROVIDER: S-EPMC2825421 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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c-Jun N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82.

Bi Wenzhi W Xiao Lei L Jia Yunfeng Y Wu Junbing J Xie Qi Q Ren Jian J Ji Guangju G Yuan Zengqiang Z

The Journal of biological chemistry 20091222 9

Protein kinases play an important role in the maintenance of homeostasis between cell survival and apoptosis. Deregulation of these kinases leads to various pathological manifestations, such as cancer and neurodegenerative diseases. The MST1 encodes a serine/threonine kinase that is activated upon apoptotic stimulation, which in turn phosphorylates its downstream targets, Histone H2B and FOXO. However, the upstream regulators of MST1 kinase have been poorly studied. In this study, we report that ...[more]

PMID: 20028971

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Project description:Cerebellar granule cell (CGC) apoptosis by trophic/potassium (TK) deprivation is a model of election to study the interplay of pro-apoptotic and pro-survival signaling pathways in neuronal cell death. In this model, the c-Jun N-terminal kinase (JNK) induces pro-apoptotic genes through the c-Jun/activator protein 1 (AP-1) transcription factor. On the other side, a survival pathway initiated by lithium leads to repression of pro-apoptotic c-Jun/AP-1 target genes without interfering with JNK activity. Yet, the mechanism by which lithium inhibits c-Jun activity remains to be elucidated. Here, we used this model system to study the regulation and function of site-specific c-Jun phosphorylation at the S63 and T91/T93 JNK sites in neuronal cell death. We found that TK-deprivation led to c-Jun multiphosphorylation at all three JNK sites. However, immunofluorescence analysis of c-Jun phosphorylation at single cell level revealed that the S63 site was phosphorylated in all c-Jun-expressing cells, whereas the response of T91/T93 phosphorylation was more sensitive, mirroring the switch-like apoptotic response of CGCs. Conversely, lithium prevented T91T93 phosphorylation and cell death without affecting the S63 site, suggesting that T91T93 phosphorylation triggers c-Jun pro-apoptotic activity. Accordingly, a c-Jun mutant lacking the T95 priming site for T91/93 phosphorylation protected CGCs from apoptosis, whereas it was able to induce neurite outgrowth in PC12 cells. Vice versa, a c-Jun mutant bearing aspartate substitution of T95 overwhelmed lithium-mediate protection of CGCs from TK-deprivation, validating that inhibition of T91/T93/T95 phosphorylation underlies the effect of lithium on cell death. Mass spectrometry analysis confirmed multiphosphorylation of c-Jun at T91/T93/T95 in cells. Moreover, JNK phosphorylated recombinant c-Jun at T91/T93 in a T95-dependent manner. On the basis of our results, we propose that T91/T93/T95 multiphosphorylation of c-Jun functions as a sensitivity amplifier of the JNK cascade, setting the threshold for c-Jun pro-apoptotic activity in neuronal cells.

Dataset Information

C-Jun N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82.

Publications

c-Jun N-terminal kinase enhances MST1-mediated pro-apoptotic signaling through phosphorylation at serine 82.

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