Signal Transduction through MAP Kinase Cascades

Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of Colorado, Boulder 80309, USA.
Advances in Cancer Research (Impact Factor: 4.26). 02/1998; 74:49-139. DOI: 10.1016/S0065-230X(08)60765-4
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ABSTRACT The chapter introduces the mitogen-activated protein (MAP) kinase (MAPK) module. The identification of MAP kinase pathways exemplifies the power of combining biochemical and genetic approaches to molecular problems. The chapter discusses the mammalian MAPK pathways—ERKl/2 and MKKl/2 pathways—and stress-activated protein kinase pathways. The regulation of MAPK pathways by protein phosphatases is discussed in the chapter describing in detail about dual specificity phosphatases, serinenhreonine phosphatases, and protein tyrosine phosphatases. The chapter explores the cellular substrates of MAP kinases, wherein it discusses about protein kinase substrates for MAPKS, nuclear transcription factors, signaling components, and cytoskeletal proteins. Responses to MAPK pathways, regulation of cell growth and transformation, and regulation of cell differentiation and development have also been summarized in the chapter. The chapter describes the yeast MAPK pathways of saccharomyces cerevisiae (Budding Yeast) and Schizosaccharomyces pombe (Fission Yeast). The chapter provides the description of the intracellular targeting and spatial regulation of MAPK pathway components, signaling complexes, and the nuclear translocation of MAPK and MKK. Eukaryotic MAPK cascades provide excellent examples of signal transduction mechanisms that embody key principles common to many, if not all, signaling pathways. Many fundamental questions remain for future studies to investigate the mechanisms by which these pathways are regulated as well as the cellular responses that they control.

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Available from: Timothy S Lewis, Jul 20, 2015
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    • "Activated Raf phosphorylates mitogen-activated protein kinase kinase (MEK) 1 and 2, which in turn phosphorylate extracellular signal-regulated kinase 1 and 2 (ERK1 and 2). ERKs and their downstream elements can function as transcriptional and translational regulators and promote cellular transformation, proliferation and survivability [28] [29] [30]. In cancers where an activating mutation of Ras protein is absent, the upstream or downstream signaling "
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    ABSTRACT: Interferon regulatory factor (IRF1) is a potent antiviral, antitumor and immune regulatory protein. Recently, we found that activated Ras/MEK inhibits antiviral response by downregulating IRF1 expression and renders cancer cells susceptible to oncolytic viruses. In this study, we sought to determine whether IRF1 downregulation underlies oncogenesis induced by Ras/MEK activation in human cancer cells. Treatment of the MEK inhibitor U0126 promoted IRF1 expression in 7 of 11 cancer cell lines we tested. IRF1 promotion was also observed in human cancer cell lines treated with different MEK inhibitors or with RNAi oligonucleotides against extracellular signal-regulated kinases (ERKs). Restoration of the expression of antitumor genes, p27 and p53 upregulated modulator of apoptosis (PUMA), by MEK inhibition was less in IRF1 shRNA knockdown cancer cells than in vector control cancer cells, suggesting that Ras/MEK targets IRF1 for the downregulation of the antitumor genes. Moreover, apoptosis induction by U0126 was significantly reduced in IRF1 shRNA knockdown cells than vector control cells. This study demonstrates that IRF1 expression is suppressed by activated Ras/MEK in human cancer cells and that IRF1 plays essential roles in apoptosis induced by Ras/MEK inhibition. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.017 · 5.02 Impact Factor
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    • "Those are the extracelluar signal-regulated protein kinase (Erk), c-Jun N-terminal kinase/stress-activated protein kinases (Jnk/Sapk) and p38 [10]. The roles of MAPKs are involved in regulating cell proliferation, cell differentiation and cell apoptosis [11] [12] [13]. MAPK kinase kinase kinase isoform 4 (MAP4K4) is known as a germinal centre protein kinases that belong to the mammalian STE20/MAP4K family [14] [15]. "
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    ABSTRACT: CD4(+) T cells are critical for adaptive immunity. MAP4K4 is a key member of germinal center kinase group. However, the physiological function of MAP4K4 in primary CD4(+) T cells is still unclear. In this study, it was demonstrated that in vitro, MAP4K4 deletion remarkably suppressed CD4(+) T cell proliferation in response to phorbol 12-myristate 13-acetate (PMA) and ionomycin, which was not due to enhancing cell apoptosis. Additionally, MAP4K4 was required for the activation of CD4(+) T cells. MAP4K4 deletion significantly down-regulated expression of interleukin 2 (IL-2) and interferon-γ (IFN-γ), while notably up-regulating the expression of regulatory T cells (Treg) transcription factor Foxp3 in peripheral CD4(+) T cells. Furthermore, western blot analysis indicated that CD4(+) T cells lacking MAP4K4 failed to phosphorylate Jnk, Erk, p38 and PKC-θ. Thus, our results provide the evidence that MAP4K4 is essential for CD4(+) T cell proliferation, activation and cytokine production.
    Cellular Immunology 03/2014; 289(1-2):15-20. DOI:10.1016/j.cellimm.2014.02.006 · 1.87 Impact Factor
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    • "Phosphorylation of plectin S4642 was hence dependent on ERK1/2 and/or ERK5. Nevertheless, they cannot directly phosphorylate plectin S4642, because of their substrate consensus motif incompatible with S4642 (Lewis et al., 1998). ERK1/2 and ERK5 activate several downstream kinases encompassing 90 kDa ribosomal S6 kinases (p90RSKs), mitogen and stress activated kinases (MSKs), and MAP-kinaseinteracting kinases (MNKs) (Cargnello and Roux, 2011). "
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    ABSTRACT: Plectin is a versatile cytolinker of the plakin family conferring cell resilience to mechanical stress in stratified epithelia and muscles. It is a critical organizer of the cytoskeletal system by tethering various intermediate filament (IF) networks through its COOH-terminal IF-binding domain (IFBD). Mutations affecting the IFBD cause devastating human diseases. Here, we have found that serine 4642, located in the COOH-extremity of plectin, is phosphorylated in different cell lines. Phosphorylation of S4642 decreased the ability of plectin IFBD to associate with various IFs, as assessed by immunofluorescence microscopy and cell fractionation studies, as well as in yeast two-hybrid assays. Plectin phosphorylated at S4642 was reduced at sites of IF network anchorage along cell-substrate contacts in both skin and cultured keratinocytes. Treatment of SK-MEL-2 and HeLa cells with okadaic acid increased plectin S4642 phosphorylation suggesting that protein phosphatase 2A dephosphorylates this residue. Moreover, plectin S4642 phosphorylation was enhanced after cell treatment with EGF, phorbol ester, sorbitol, 8-bromo-cyclic AMP, as well as during wound healing and protease-mediated cell detachment. Using selective protein kinase inhibitors, we identified two different kinases modulating the phosphorylation of plectin S4642 in HeLa cells, MNK2, downstream the ERK1/2-dependent MAPK cascade, and PKA. Our study indicates that phosphorylation of S4642 has an important regulatory role in the interaction of plectin with IFs and identifies a novel link between MNK2 and the cytoskeleton.
    Journal of Cell Science 07/2013; 126(18). DOI:10.1242/jcs.127779 · 5.33 Impact Factor
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