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: 5.32). 02/1998; 74:49-139. DOI: 10.1016/S0065-230X(08)60765-4
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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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    • "At this concentration, AG1478 was found to exert a low level of cytotoxicity on HK-1 cells. It is well documented that EGFR activates survival signaling pathways namely PI3K/Akt [Chan et al., 1999; Vivanco and Sawyers, 2002] and ERKs [Lewis et al., 1998]. In order to elucidate the downstream pathways of EGFR in HK-1 cells, the cells were incubated with 10 mM of AG1478 for 2 h. "
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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 · 5.62 Impact Factor
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    • "Mitogen-activated protein kinase (MAPK) cascades, which are widely distributed in eukaryotes, have an important function in the diverse developmental and physiological processes of plants, and in response to various biotic and abiotic stresses [1], [2]. Each MAPK cascade consists of three protein kinases: MAPKs, MAPK kinases (MAPKKs/MKKs), and MAPKK kinases (MAPKKKs/MEKKs). "
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    ABSTRACT: Mitogen-activated protein kinase (MAPK) cascades have important functions in plant growth, development, and response to various stresses. The MAPKK and MAPKKK gene families in tomato have never been systematically analyzed. In this study, we performed a genome-wide analysis of the MAPKK and MAPKKK gene families in tomato and identified 5 MAPKK genes and 89 MAPKKK genes. Phylogenetic analyses of the MAPKK and MAPKKK gene families showed that all the MAPKK genes formed four groups (groups A, B, C, and D), whereas all the MAPKKK genes were classified into three subfamilies, namely, MEKK, RAF, and ZIK. Evolutionary analysis showed that whole genome or chromosomal segment duplications were the main factors responsible for the expansion of the MAPKK and MAPKKK gene families in tomato. Quantitative real-time RT-PCR analysis showed that the majority of MAPKK and MAPKKK genes were expressed in all tested organs with considerable differences in transcript levels indicating that they might be constitutively expressed. However, the expression level of most of these genes changed significantly under heat, cold, drought, salt, and Pseudomonas syringae treatment. Furthermore, their expression levels exhibited significant changes in response to salicylic acid and indole-3-acetic acid treatment, implying that these genes might have important roles in the plant hormone network. Our comparative analysis of the MAPKK and MAPKKK families would improve our understanding of the evolution and functional characterization of MAPK cascades in tomato.
    PLoS ONE 07/2014; 9(7):e103032. DOI:10.1371/journal.pone.0103032 · 3.23 Impact Factor
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