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, Aug 12, 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 · 5.62 Impact Factor
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    • "p - or down - regulation of p53 , Bax , and Bcl - 2 levels , as well as activation of cleaved caspase - 9 , cleaved caspase - 3 , and cleaved PARP . MAPKs control many cellular events , including differentiation , proliferation , and apoptosis , and to date at least three major MAPK subfamilies have been characterized , JNK , ERK 1 / 2 , and p38 ( Lewis et al . , 1998 ) . Also , a growing body of evidence suggests that phos - phorylation of PI3K / Akt and GSK - 3b pathways is a key step in diverse biological processes , including proliferation , growth , sur - vival , and apoptosis ( Chen et al . , 2004 ; Ikeda et al . , 2008 ; Li et al . , 2011 ; Schroeter et al . , 2002 ) . In particular , MAPK , P"
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    ABSTRACT: Sulfuretin, a potent anti-oxidant, has been thought to provide health benefits by decreasing the risk of oxidative stress-related diseases. In this study, we investigated the mechanisms of sulfuretin protection of neuronal cells from cell death induced by the Parkinson's disease (PD)-related neurotoxin 6-hydroxydopamine (6-OHDA). We examined whether sulfuretin acts as an anti-oxidant to reduce oxidative stress and mitochondrial-mediated apoptotic cascade events in 6-OHDA-induced neurotoxicity in SH-SY5Y cells. We also investigated whether sulfuretin specifically acts by inhibiting phosphorylation of mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and glycogen synthase kinase-3beta (GSK-3β) as well as activation of the nuclear factor-κappa B (NF-κB) pathway. Sulfuretin significantly inhibited neuronal cell death, neurotoxicity, apoptosis, and reactive oxygen species (ROS) production. Sulfuretin also strikingly attenuated 6-OHDA-induced mitochondrial dysfunction. Moreover, sulfuretin significantly attenuated 6-OHDA-induced phosphorylation of c-Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase 1/2 (ERK 1/2) MAPKs, PI3K/Akt, and GSK-3β. Eventually, sulfuretin inhibited 6-OHDA-induced NF-κB translocation to the nucleus induced by 6-OHDA. The results of the current study provide the first evidence that sulfuretin protects SH-SY5Y cells against 6-OHDA-induced neuronal cell death, possibly through inhibition of phosphorylation of MAPK, PI3K/Akt, and GSK-3β, which leads to mitochondrial protection, NF-κB modulations and subsequent suppression of apoptosis via ROS-dependent pathways. Thus, we conclude that sulfuretin may have a potential role for neuroprotection and, therefore, may be used as a therapeutic agent for PD.
    Neurochemistry International 05/2014; 74. DOI:10.1016/j.neuint.2014.04.016 · 2.65 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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