MAP kinases and the control of nuclear events

Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
Oncogene (Impact Factor: 8.46). 06/2007; 26(22):3240-53. DOI: 10.1038/sj.onc.1210415
Source: PubMed

ABSTRACT The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that play an essential role in signal transduction by modulating gene transcription in the nucleus in response to changes in the cellular environment. They include the extracellular signal-regulated protein kinases (ERK1 and ERK2); c-Jun N-terminal kinases (JNK1, JNK2, JNK3); p38s (p38alpha, p38beta, p38gamma, p38delta) and ERK5. The molecular events in which MAPKs function can be separated in discrete and yet interrelated steps: activation of the MAPK by their upstream kinases, changes in the subcellular localization of MAPKs, and recognition, binding and phosphorylation of MAPK downstream targets. The resulting pattern of gene expression will ultimately depend on the integration of the combinatorial signals provided by the temporal activation of each group of MAPKs. This review will focus on how the specificity of signal transmission by MAPKs is achieved by scaffolding molecules and by the presence of structural motifs in MAPKs that are dynamically regulated by phosphorylation and protein-protein interactions. We discuss also how MAPKs recognize and phosphorylate their target nuclear proteins, including transcription factors, co-activators and repressors and chromatin-remodeling molecules, thereby affecting an intricate balance of nuclear regulatory molecules that ultimately control gene expression in response to environmental cues.

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Available from: Adrian Gustavo Turjanski, Sep 27, 2015
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    • "N-terminal kinase (JNK), and p38 [16]. Previous studies have demonstrated that H. pylori-induced activation of MAPK mediates IL-8 expression by increasing NF-í µí¼…B and AP-1 DNA-binding activities [17] [18]. "
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    ABSTRACT: Helicobacter pylori is an important risk factor for gastric inflammation, which is mediated by multiple signaling pathways. The aim of this study was to investigate the effects of polyunsaturated fatty acids (PUFAs), such as linoleic acid (LA), alpha-linolenic acid (ALA), and docosahexaenoic acid (DHA), on the expression of the proinflammatory chemokine interleukin-8 (IL-8) in H. pylori-infected gastric epithelial AGS cells. To investigate whether PUFAs modulate H. pylori-induced inflammatory signaling, we determined the activation of epidermal growth factor receptor (EGFR), protein kinase C- δ (PKC δ ), mitogen-activated protein kinases (MAPKs), nuclear factor-kappa B (NF- κ B), and activator protein-1 (AP-1) as well as IL-8 expression in H. pylori-infected gastric epithelial cells that had been treated with or without PUFAs. We found that PUFAs inhibited IL-8 mRNA and protein expression in H. pylori-infected cells. ω -3 fatty acids (ALA, and DHA) suppressed the activation of EGFR, PKC δ , MAPK, NF- κ B, and AP-1 in these infected cells. LA did not prevent EGFR transactivation and exhibited a less potent inhibitory effect on IL-8 expression than did ALA and DHA. In conclusion, PUFAs may be beneficial for prevention of H. pylori-associated gastric inflammation by inhibiting proinflammatory IL-8 expression.
    Mediators of Inflammation 06/2014; 2014(196):128919. DOI:10.1155/2014/128919 · 3.24 Impact Factor
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    • "Several p38-MAPK isoforms other than p38a exist and are involved in stress signaling and apoptosis (Cuadrado and Nebreda, 2010; Turjanski et al., 2007). Thus, we examined if Mnk2a enhances the phosphorylation of other p38-MAPK family members when cotransfected into HeLa cells. "
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    ABSTRACT: The kinase Mnk2 is a substrate of the MAPK pathway and phosphorylates the translation initiation factor eIF4E. In humans, MKNK2, the gene encoding for Mnk2, is alternatively spliced yielding two splicing isoforms with differing last exons: Mnk2a, which contains a MAPK-binding domain, and Mnk2b, which lacks it. We found that the Mnk2a isoform is downregulated in breast, lung, and colon tumors and is tumor suppressive. Mnk2a directly interacts with, phosphorylates, activates, and translocates p38α-MAPK into the nucleus, leading to activation of its target genes, increasing cell death and suppression of Ras-induced transformation. Alternatively, Mnk2b is pro-oncogenic and does not activate p38-MAPK, while still enhancing eIF4E phosphorylation. We further show that Mnk2a colocalization with p38α-MAPK in the nucleus is both required and sufficient for its tumor-suppressive activity. Thus, Mnk2a downregulation by alternative splicing is a tumor suppressor mechanism that is lost in some breast, lung, and colon tumors.
    Cell Reports 04/2014; 7(2). DOI:10.1016/j.celrep.2014.03.041 · 8.36 Impact Factor
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    • "In particular, the precise nature of the extracellular stimuli and the repertoire of molecules available in each cell type can determine the localization, timing, intensity and duration of the activation of each Figure 8 uPAR and Cathepsin B mediated migration of glioma cells. member of the MAPK family (Raman et al., 2007; Turjanski et al., 2007). Several reports indicate the involvement of MAPKs in gene expression, proliferation, motility, metabolism and apoptosis (Cuevas et al., 2007; Dhillon et al., 2007; Huang et al., 2004b; Qi and Elion, 2005). "
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    ABSTRACT: In the present study, we investigated the effect of simultaneous downregulation of uPAR and cathepsin B (pUC), alone or in combination with radiation, on JNK-MAPK signaling pathway in regulating the migration of non-GICs (glioma-initiating cells) and GICs. The increase in the expression of p-JNK with pUC treatment was mostly localized to nucleus whereas increase in the expression of p-JNK with radiation and overexpression of uPAR and cathepsin B was confined to cytoplasm of the cells. Depletion of cytosolic p-JNK with pUC treatment inhibited migration by downregulating the expression of the adapter proteins of the focal adhesion complex. We also observed that knockdown of uPAR and cathepsin B regulated the Ras-Pak-1 pathway to induce the translocation of p-JNK from cytosol to nucleus. In control cells, Pak-1 served as a functional inhibitor for MEKK-1, which inhibits the complex formation of MEKK-1 and p-JNK and thus inhibits the translocation of this complex into nucleus. Hence, we conclude that glioma cells utilize the availability of cytosolic p-JNK in driving the cells towards migration. Finally, treating the cells with pUC alone or in combination with radiation induced the translocation of the MEKK-1-p-JNK complex from cytosol to nucleus, thereby inhibiting the migration of glioma cells.
    Stem Cell Research 03/2014; 12(3):716-729. DOI:10.1016/j.scr.2014.02.008 · 3.69 Impact Factor
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