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Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis.

ABSTRACT: Activation of the c-JUN N-terminal kinase (JNK) pathway is implicated in a number of important physiological processes, from embryonic morphogenesis to cell survival and apoptosis. JNK stimulatory phosphatase 1 (JSP1) is a member of the dual-specificity phosphatase subfamily of protein tyrosine phosphatases. In contrast to other dual-specificity phosphatases that catalyze the inactivation of mitogen-activated protein kinases, expression of JSP1 activates JNK-mediated signaling. JSP1 and its relative DUSP15 are unique among members of the protein tyrosine phosphatase family in that they contain a potential myristoylation site at the N-terminus (MGNGMXK). In this study, we investigated whether JSP1 was myristoylated and examined the functional consequences of myristoylation. Using mass spectrometry, we showed that wild-type JSP1, but not a JSP1 mutant in which Gly2 was mutated to Ala (JSP1-G2A), was myristoylated in cells. Although JSP1 maintained intrinsic phosphatase activity in the absence of myristoylation, the subcellular localization of the enzyme was altered. Compared with the wild type, the ability of nonmyristoylated JSP1 to induce JNK activation and phosphorylation of the transcription factor c-JUN was attenuated. Upon expression of wild-type JSP1, a subpopulation of cells, with the highest levels of the phosphatase, was induced to float off the dish and undergo apoptosis. In contrast, cells expressing similar levels of JSP1-G2A remained attached, further highlighting that the myristoylation mutant was functionally compromised.

SUBMITTER: Schwertassek U

PROVIDER: S-EPMC2894504 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis.

Schwertassek Ulla U Buckley Deirdre A DA Xu Chong-Feng CF Lindsay Andrew J AJ McCaffrey Mary W MW Neubert Thomas A TA Tonks Nicholas K NK

The FEBS journal 20100601 11

Activation of the c-JUN N-terminal kinase (JNK) pathway is implicated in a number of important physiological processes, from embryonic morphogenesis to cell survival and apoptosis. JNK stimulatory phosphatase 1 (JSP1) is a member of the dual-specificity phosphatase subfamily of protein tyrosine phosphatases. In contrast to other dual-specificity phosphatases that catalyze the inactivation of mitogen-activated protein kinases, expression of JSP1 activates JNK-mediated signaling. JSP1 and its rela ...[more]

PMID: 20553486

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Project description:Oxidative stress has been associated with neuronal loss in neurodegenerative diseases and during age-associated cognitive decline. Flavonoids have been proposed to play a useful role in protecting the central nervous system against oxidative and excitotoxic stress, although the mechanism of action is unknown. Using oxidized low-density lipoprotein (oxLDL) as the oxidative insult we investigated the mechanism of neurotoxicity and attempted to identify possible sites of action of two of the most potent protective flavonoids, epicatechin and kaempferol, in cultured primary neurons. Using cultured striatal neurons and selective phosphospecific antibodies we addressed the potential role of extracellular signal-regulated kinases 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK). OxLDL stimulated a Ca(2+)-dependent activation of both ERK1/2 and JNK that was strongly inhibited by pre-treatment with low micromolar concentrations of epicatechin. Neurotoxicity induced by oxLDL, however, was neither reduced nor enhanced by inhibiting ERK1/2 activation with mitogen-activated protein kinase kinase (MEK) inhibitors, suggesting that this cascade is unlikely to be involved in either oxLDL toxicity or the protective effects of flavonoids. oxLDL caused a sustained activation of JNK that resulted in the phosphorylation of the transcription factor c-Jun, which was abolished in neurons pre-treated with flavonoids. Furthermore, oxLDL induced the cleavage of procaspase-3 and increased caspase-3-like protease activity in neurons, an effect which was strongly inhibited by pre-exposure to either epicatechin or kaempferol. In addition, a caspase-3 inhibitor reduced oxLDL-induced neuronal death, implicating an apoptotic mechanism. A major in vivo metabolite of epicatechin, 3'-O-methyl-epicatechin was as effective as epicatechin in protecting neurons. Thus dietary flavonoids might have potential as protective agents against neuronal apoptosis through selective actions within stress-activated cellular responses, including protein kinase signalling cascades.

Dataset Information

Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis.

Publications

Myristoylation of the dual-specificity phosphatase c-JUN N-terminal kinase (JNK) stimulatory phosphatase 1 is necessary for its activation of JNK signaling and apoptosis.

Similar Datasets

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