DOCSLIB.ORG

Roles of Induced Expression of MAPK Phosphatase-2 in Tumor Development in RET-MEN2A Transgenic Mice

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Roles of Induced Expression of MAPK Phosphatase-2 in Tumor Development in RET-MEN2A Transgenic Mice Oncogene (2008) 27, 5684–5695 & 2008 Macmillan Publishers Limited All rights reserved 0950-9232/08 $32.00 www.nature.com/onc ORIGINAL ARTICLE Roles of induced expression of MAPK phosphatase-2 in tumor development in RET-MEN2A transgenic mice T Hasegawa1,2, A Enomoto1,3, T Kato1, K Kawai1, R Miyamoto1, M Jijiwa1, M Ichihara4, M Ishida1, N Asai1, YMurakumo 1, K Ohara1,2, YNiwa 2, H Goto2 and M Takahashi1,5 1Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 2Department of Gastroenterology, Nagoya University Graduate School of Medicine, Nagoya, Japan; 3Institute for Advanced Research, Nagoya University, Nagoya, Japan; 4Department of Biomedical Sciences, College of Life and Health Sciences, Chubu University, Kasugai, Japan and 5Division of Molecular Pathology, Center for Neurological Disease and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Japan Germline mutations in the RET tyrosine kinase gene are line-derived neurotrophic factor (GDNF) family responsible for the development of multiple endocrine of ligands (GFLs). It has a crucial role in transducing neoplasia 2A and 2B (MEN2A and MEN2B). However, growth and differentiation signals in tissues knowledge of the fundamental principles that determine derived from the neural crest and the developing kidney the mutant RET-mediated signaling remains elusive. (Schuchardt et al., 1994; Moore et al., 1996; Pichel Here, we report increased expression of mitogen-activated et al., 1996; Sa´ nchez et al., 1996; Treanor et al., 1996; protein kinase phosphatase-2 (MKP-2) in carcinomas Rosenthal, 1999; Airaksinen and Saarma, 2002). developed in transgenic mice carrying RET with the It has been firmly established that germline mutations MEN2A mutation (RET-MEN2A). The expression of in the RET gene are responsible for several forms of MKP-2 was not only induced by RET-MEN2A or RET- human diseases. RET loss-of-function mutations MEN2B mutant proteins but also by the activation of predispose for enteric neural crest cell dysfunction, endogenous RET by its ligand, glial cell line-derived which leads to Hirschsprung’s disease, whereas its gain- neurotrophic factor (GDNF). MKP-2 expression was also of-function mutations are found in several human evident in the MKK-f cell line, which was established from cancers, including multiple endocrine neoplasia (MEN) a mammary tumor developed in a RET-MEN2A trans- type 2A (MEN2A) and 2B (MEN2B), familial medul- genic mouse. Inhibition of MKP-2 attenuated the in vitro lary thyroid carcinoma (FMTC) and papillary thyroid and in vivo proliferation of MKK-f cells, which was carcinoma (Donis-Keller et al., 1993; Mulligan et al., mediated by the suppression of cyclin B1 expression. 1993; Carlson et al., 1994; Edery et al., 1994; Hofstra Furthermore, we found that MKP-2 is highly expressed in et al., 1994; Romeo et al., 1994). The MEN2A medullary thyroid carcinomas derived from MEN2A mutations were identified primarily in cysteine residues patients. These findings suggest that the increased of the RET extracellular domain that lead to ligand- expression of MKP-2 may play a crucial role in oncogenic independent RET dimerization via the formation signaling downstreamof mutant RET, leading to dereg- of an intermolecular disulfide bond (Asai et al., 1995; ulation of cell cycle. Santoro et al., 1995; Eng, 1999). The MEN2B muta- Oncogene (2008) 27, 5684–5695; doi:10.1038/onc.2008.182; tions, characterized by a methionine-to-threonine published online 9 June 2008 change at codon 918 or an alanine-to-phenylalanine change at codon 883 in the tyrosine kinase domain, Keywords: RET; MEN2A; MKP-2; cell proliferation; result in an increase of intrinsic RET catalytic activity cell cycle (Carlson et al., 1994; Gimm et al., 1997; Smith et al., 1997). Of particular interest are marked differences in affected organs and disease phenotype among indivi- duals and kindreds with MEN2A, MEN2B or FMTC Introduction mutations (Kodama et al., 2005; Asai et al., 2006). MEN2A is characterized by MTC, pheochromocytoma The RET proto-oncogene encodes a receptor tyrosine and parathyroid adenoma, whereas MEN2B shows a kinase that acts as a functional receptor for the glial cell more complex phenotype, with association of MTC, pheochromocytoma, mucosal neuroma, intestinal gang- lioneuromatosis and skeletal deformity. FMTC patients Correspondence: Professor M Takahashi, Department of Pathology, develop MTC only. The diversity and complexity of the Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, phenotypes observed with MEN2A, MEN2B and Showa-ku, Nagoya, Aichi 466-8550, Japan. E-mail: [email protected] FMTC patients suggest that the mutant RET protein Received 8 January 2008; revised 14 April 2008; accepted 7 May 2008; is responsible for distinct patterns of intracellular published online 9 June 2008 signaling cascades. Roles of MKP-2 in RET-MEN2A-induced tumorigenesis T Hasegawa et al 5685 Previous studies have revealed that constitutive To define the genes that are potentially involved in phosphorylation of tyrosine residues in the intracellular tumorigenesis in RET-MEN2A transgenic mice, we domains of RET-MEN2A and RET-MEN2B mutant compared gene expression between pooled carcinomas proteins results in activation of the Ras/Raf/mitogen- and normal tissues from six independent mice using activated protein kinase (MAPK), phosphatidylinositol- cDNA microarrays (Table 1). The expression levels of 3 kinase/Akt, p38 MAPK and c-Jun amino-terminal 11 genes were upregulated more than twofold (log ratio) kinase (JNK) pathways (Takahashi, 2001; Airaksinen in all of the carcinoma tissues (thyroid, salivary and and Saarma, 2002; Kodama et al., 2005; Asai et al., mammary carcinomas). Validation of the microarray 2006). Because all of these pathways are also activated results with quantitative reverse transcription (RT)-PCR by the GFLs via endogenous RET, the question arises as showed that 7 of the 11 genes showed similar trends or to how the signals downstream of the RET mutants are much higher expression levels when compared with the distinct from those promoted by normal RET, in which microarray data. These seven genes were mouse Ret, the duration and strength of signals are tightly Col11a1, Cxcl1, Usp18, Slc35d3, MKP-2 and Tde2l regulated. (Table 1). To elucidate the developmental mechanisms of the MEN2A phenotype, we established transgenic mice expressing RET-MEN2A that developed salivary, thyr- Induction of MKP-2 expression by RET-MEN2A, oid and mammary gland carcinomas (Kawai et al., RET-MEN2B or normal RET activation 2000). In this study, cDNA microarrays were used to MKP-2 (also termed DUSP4), a dual-specificity phos- analyse global gene expression patterns in salivary, phatase that possesses phosphatase activity toward thyroid and mammary carcinomas to identify potential MAPKs (p42/44 MAPK, p38 MAPK and JNK) molecular determinants of RET-MEN2A-dependent (Farooq and Zhou, 2004; Dickinson and Keyse, 2006; tumorigenesis. MAPK phosphatase-2 (MKP-2; Owens and Keyse, 2007) was chosen for further study. DUSP4), one of the genes that was upregulated in all The expression levels of the MKP-2 protein were the carcinomas was chosen for further study. MKP-2 examined by immunostaining sections from the mam- was first identified as a dual-specificity phosphatase that mary and salivary carcinomas and normal tissues from selectively dephosphorylates the p42/44 MAPK, p38 RET-MEN2A transgenic mice (Figure 1a). Consistent MAPK and JNK (Guan and Butch, 1995; Misra-Press with the microarray analysis, MKP-2 expression was not et al., 1995; Farooq and Zhou, 2004; Cadalbert et al., detected in the ductal epithelial cells of the normal 2005; Dickinson and Keyse, 2006; Owens and Keyse, mammary and salivary glands but was highly expressed 2007). Interestingly, despite the activity of MKP-2 in in the mammary and salivary carcinomas. MKP-2 inhibiting the activity of the MAPKs, depletion of immunoreactivity was detected predominantly in the MKP-2 by RNA interference resulted in deregulation of cytoplasm and weakly in the nucleus. the cell cycle and proliferative inhibition of MKK-f, a We next examined whether the expression of MKP-2 cell line that was established from a mammary is induced by the overexpression of mutant RET carcinoma developed in a RET-MEN2A transgenic protein. MKP-2 transcript and protein expression were mouse (Kawai et al., 2003). We also found that the significantly upregulated in NIH3T3 cells that stably expression of MKP-2 was induced downstream of expressed RET-MEN2A or RET-MEN2B (Figures 1b GDNF activation of normal RET in a temporally and c). MEF3T3 lines that express RET-MEN2A and regulated manner that may orchestrate the tempo and RET-MEN2B under the control of a tetracycline- duration of MAPK activation in a physiological suppressible (Tet-off) promoter were also used to context. These data suggest that constitutively induced examine the effect of mutant RET on MKP-2 expres- expression and activity of MKP-2 may be necessary to sion. At 2 days after the induction of RET, the levels of maintain continuous proliferation of RET-MEN2A- MKP-2 mRNA and protein were analysed by semi- driven carcinomas and present a previously unrecog- quantitative RT–PCR and western blot analysis, respec- nized role for MKP-2. tively. As shown in Figures 1d and e, MKP-2 mRNA and protein were induced over a time course similar to that of RET induction. The expression of MKP-2 was also apparent in the MKK-f cell line, which was Results established from mammary carcinoma from a RET- MEN2A transgenic mouse (Kawai et al., 2003) (Figures Analysis of gene expression in carcinomas from 1b and c). These results indicate that mutant RET is RET-MEN2A transgenic mice capable of inducing MKP-2 expression. We previously reported the establishment of RET- To investigate whether MKP-2 expression is induced MEN2A transgenic mice, which express a recombinant by the activation of endogenous RET by GDNF, TGW human RET-MEN2A gene (Cys634-Arg) driven by neuroblastoma cells, which have been shown to express Moloney murine leukemia virus long terminal repeat both endogenous RET and GFRa1 (Watanabe et al., (MoMuLV LTR) (Kawai et al., 2000).
Load more

Recommended publications
  • Plant Mitogen-Activated Protein Kinase Signaling Cascades Guillaume Tena*, Tsuneaki Asai†, Wan-Ling Chiu‡ and Jen Sheen§
    392 Plant mitogen-activated protein kinase signaling cascades Guillaume Tena*, Tsuneaki Asai†, Wan-Ling Chiu‡ and Jen Sheen§ Mitogen-activated protein kinase (MAPK) cascades have components that link sensors/receptors to target genes emerged as a universal signal transduction mechanism that and other cellular responses. connects diverse receptors/sensors to cellular and nuclear responses in eukaryotes. Recent studies in plants indicate that In the past few years, it has become apparent that mitogen- MAPK cascades are vital to fundamental physiological functions activated protein kinase (MAPK) cascades play some of the involved in hormonal responses, cell cycle regulation, abiotic most essential roles in plant signal transduction pathways stress signaling, and defense mechanisms. New findings have from cell division to cell death (Figure 1). MAPK cascades revealed the complexity and redundancy of the signaling are evolutionarily conserved signaling modules with essen- components, the antagonistic nature of distinct pathways, and tial regulatory functions in eukaryotes, including yeasts, the use of both positive and negative regulatory mechanisms. worms, flies, frogs, mammals and plants. The recent enthu- siasm for plant MAPK cascades is backed by numerous Addresses studies showing that plant MAPKs are activated by hor- Department of Molecular Biology, Massachusetts General Hospital, mones, abiotic stresses, pathogens and pathogen-derived Department of Genetics, Harvard Medical School, Wellman 11, elicitors, and are also activated at specific stages during the 50 Blossom Street, Boston, Massachusetts 02114, USA cell cycle [2]. Until recently, studies of MAPK cascades in *e-mail: [email protected] †e-mail: [email protected] plants were focused on cDNA cloning [3,4] and used a ‡e-mail: [email protected] MAPK in-gel assay, MAPK and tyrosine-phosphate anti- §e-mail: [email protected] bodies, and kinase inhibitors to connect signals to MAPKs Current Opinion in Plant Biology 2001, 4:392–400 [2].
    [Show full text]
  • ERK Cascade Pathway
    Biochemistry and Biophysics Reports 7 (2016) 10–19 Contents lists available at ScienceDirect Biochemistry and Biophysics Reports journal homepage: www.elsevier.com/locate/bbrep Glutamine up-regulates MAPK phosphatase-1 induction via activation of Ca2 þ- ERK cascade pathway Otgonzaya Ayush a, Zhe Wu Jin c, Hae-Kyoung Kim b, Yu-Rim Shin d, Suhn-Young Im e, Hern-Ku Lee b,n a Department of Dermatology, Medical University, Mongolian National University of Medical Sciences, Ulaanbaatar, Mongolia b Departments of Immunology and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Republic of Korea c Department of Anatomy and Histology and Embryology, Yanbian University Medical College, YanJi City, Jilin Province, China d Biofoods Story, Inc, 477 Jeonjucheon-seoro, Wansan-gu, Jeonju, Jeonbuk 560-821, Republic of Korea e Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, Republic of Korea article info abstract Article history: The non-essential amino acid L-glutamine (Gln) displays potent anti-inflammatory activity by deacti- Received 3 February 2016 vating p38 mitogen activating protein kinase and cytosolic phospholipase A2 via induction of MAPK Received in revised form phosphatase-1 (MKP-1) in an extracellular signal-regulated kinase (ERK)-dependent way. In this study, 9 May 2016 the mechanism of Gln-mediated ERK-dependency in MKP-1 induction was investigated. Gln increased Accepted 11 May 2016 ERK phosphorylation and activity, and phosphorylations of Ras, c-Raf, and MEK, located in the upstream Available online 12 May 2016 pathway of ERK, in response to lipopolysaccharidein vitro and in vivo. Gln-induced dose-dependent 2 þ Keywords: transient increases in intracellular calcium ([Ca ]i) in MHS macrophage cells.
    [Show full text]
  • Lipopolysaccharide Macrophage Responses to Tristetraprolin
    Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide This information is current as of August 28, 2019. Tim Smallie, Ewan A. Ross, Alaina J. Ammit, Helen E. Cunliffe, Tina Tang, Dalya R. Rosner, Michael L. Ridley, Downloaded from Christopher D. Buckley, Jeremy Saklatvala, Jonathan L. Dean and Andrew R. Clark J Immunol 2015; 195:277-288; Prepublished online 27 May 2015; http://www.jimmunol.org/ doi: 10.4049/jimmunol.1402830 http://www.jimmunol.org/content/195/1/277 Supplementary http://www.jimmunol.org/content/suppl/2015/05/27/jimmunol.140283 Material 0.DCSupplemental at Aston Univ - SciTech Faculty Team on August 28, 2019 References This article cites 65 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/195/1/277.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2015 The Authors All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Dual-Specificity Phosphatase 1 and Tristetraprolin Cooperate To Regulate Macrophage Responses to Lipopolysaccharide Tim Smallie,*,1 Ewan A.
    [Show full text]
  • Dual-Specificity Phosphatases in Immunity and Infection
    International Journal of Molecular Sciences Review Dual-Specificity Phosphatases in Immunity and Infection: An Update Roland Lang * and Faizal A.M. Raffi Institute of Clinical Microbiology, Immunology and Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054 Erlangen, Germany * Correspondence: [email protected]; Tel.: +49-9131-85-22979 Received: 15 May 2019; Accepted: 30 May 2019; Published: 2 June 2019 Abstract: Kinase activation and phosphorylation cascades are key to initiate immune cell activation in response to recognition of antigen and sensing of microbial danger. However, for balanced and controlled immune responses, the intensity and duration of phospho-signaling has to be regulated. The dual-specificity phosphatase (DUSP) gene family has many members that are differentially expressed in resting and activated immune cells. Here, we review the progress made in the field of DUSP gene function in regulation of the immune system during the last decade. Studies in knockout mice have confirmed the essential functions of several DUSP-MAPK phosphatases (DUSP-MKP) in controlling inflammatory and anti-microbial immune responses and support the concept that individual DUSP-MKP shape and determine the outcome of innate immune responses due to context-dependent expression and selective inhibition of different mitogen-activated protein kinases (MAPK). In addition to the canonical DUSP-MKP, several small-size atypical DUSP proteins regulate immune cells and are therefore also reviewed here. Unexpected and complex findings in DUSP knockout mice pose new questions regarding cell type-specific and redundant functions. Another emerging question concerns the interaction of DUSP-MKP with non-MAPK binding partners and substrate proteins.
    [Show full text]
  • Dual-Specificity Phosphatases 2
    Genes and Immunity (2013) 14, 1–6 & 2013 Macmillan Publishers Limited All rights reserved 1466-4879/13 www.nature.com/gene REVIEW Dual-specificity phosphatases 2: surprising positive effect at the molecular level and a potential biomarker of diseases WWei1,2, Y Jiao2,3, A Postlethwaite4,5, JM Stuart4,5, Y Wang6, D Sun1 and W Gu2 Dual-specificity phosphatases (DUSPs) is an emerging subclass of the protein tyrosine phosphatase gene superfamily, a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/ phosphothreonine residues within the one substrate. Recently, a series of investigations of DUSPs defined their essential roles in cell proliferation, cancer and the immune response. This review will focus on DUSP2, its involvement in different diseases and its potential as a therapeutic target. Genes and Immunity (2013) 14, 1–6; doi:10.1038/gene.2012.54; published online 29 November 2012 Keywords: dual-specificity phosphatases; disease; mitogen-activated protein kinase; immune INTRODUCTION extracellular stimuli. Inducible nucleuses MKPs include DUSP1, Mitogen-activated protein kinase (MAPK) activation cascades DUSP2, DUSP4 and DUSP5, which originated from a common mediate various physiological processes, such as cell proliferation, ancestral gene. They were shown to dephosphorylate Erks, Jnk differentiation, stress responses, inflammation, apoptosis and and p38 MAPKs to the same extent and to be induced by growth immune defense.1–4 Dysregulation of MAPK activation cascades or stress signals. DUSP6, DUSP7 and DUSP9 are cytoplasmic Erk- has been implicated in various diseases and has been the focus of specific MPKs, which can preferentially recognize Erk1 and Erk2 extensive research.5–7 MAPKs are grouped into three major classes in vitro.
    [Show full text]
  • Kinase Signaling Cascades in the Mitochondrion: a Matter of Life Or Death$
    Free Radical Biology & Medicine 38 (2005) 2–11 www.elsevier.com/locate/freeradbiomed Serial Review: The powerhouse takes control of the cell: The role of mitochondria in signal transduction Serial Review Editor: Victor Darley-Usmar Kinase signaling cascades in the mitochondrion: a matter of life or death$ Craig Horbinski, Charleen T. Chu* Division of Neuropathology, Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA Received 15 July 2004; accepted 22 September 2004 Available online 27 October 2004 Abstract In addition to powering energy needs of the cell, mitochondria function as pivotal integrators of cell survival/death signals. In recent years, numerous studies indicate that each of the major kinase signaling pathways can be stimulated to target the mitochondrion. These include protein kinase A, protein kinase B/Akt, protein kinase C, extracellular signal-regulated protein kinase, c-Jun N-terminal kinase, and p38 mitogen- activated protein kinase. Although most studies focus on phosphorylation of pro- and antiapoptotic proteins (BAD, Bax, Bcl-2, Bcl-xL), kinase- mediated regulation of complex I activity, anion and cation channels, metabolic enzymes, and Mn-SOD mRNA has also been reported. Recent identification of a number of scaffold proteins (AKAP, PICK, Sab) that bring specific kinases to the cytoplasmic surface of mitochondria further emphasizes the importance of mitochondrial kinase signaling. Immunogold electron microscopy, subcellular fractionation, and immuno- fluorescence studies demonstrate the presence of kinases within subcompartments of the mitochondrion, following diverse stimuli and in neurodegenerative diseases. Given the sensitivity of these signaling pathways to reactive oxygen and nitrogen species, in situ activation of mitochondrial kinases may represent a potent reverse-signaling mechanism for communication of mitochondrial status to the rest of the cell.
    [Show full text]
  • The Dual-Specificity Phosphatase 10 (DUSP10)
    International Journal of Molecular Sciences Review The Dual-Specificity Phosphatase 10 (DUSP10): Its Role in Cancer, Inflammation, and Immunity Marta Jiménez-Martínez 1,2,3, Konstantinos Stamatakis 1,2,3 and Manuel Fresno 1,2,3,* 1 Department of Cell Biology and Immunology, Centro de Biología Molecular ‘Severo Ochoa’ (CSIC-UAM), 28049 Madrid, Spain; [email protected] (M.J.-M.); [email protected] (K.S.) 2 Department of Molecular Biology, Universidad Autónoma de Madrid, 28049 Madrid, Spain 3 Instituto de Investigación Sanitaria la Princesa (IIS-P), 28006 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-911-964-565 Received: 13 February 2019; Accepted: 30 March 2019; Published: 1 April 2019 Abstract: Cancer is one of the most diagnosed diseases in developed countries. Inflammation is a common response to different stress situations including cancer and infection. In those processes, the family of mitogen-activated protein kinases (MAPKs) has an important role regulating cytokine secretion, proliferation, survival, and apoptosis, among others. MAPKs regulate a large number of extracellular signals upon a variety of physiological as well as pathological conditions. MAPKs activation is tightly regulated by phosphorylation/dephosphorylation events. In this regard, the dual-specificity phosphatase 10 (DUSP10) has been described as a MAPK phosphatase that negatively regulates p38 MAPK and c-Jun N-terminal kinase (JNK) in several cellular types and tissues. Several studies have proposed that extracellular signal-regulated kinase (ERK) can be also modulated by DUSP10. This suggests a complex role of DUSP10 on MAPKs regulation and, in consequence, its impact in a wide variety of responses involved in both cancer and inflammation.
    [Show full text]
  • The P38 MAPK Pathway in Rheumatoid Arthritis: a Sideways Look Andrew R
    The Open Rheumatology Journal, 2012, 6, (Suppl 2: M2) 209-219 209 Open Access The p38 MAPK Pathway in Rheumatoid Arthritis: A Sideways Look Andrew R. Clark* and Jonathan L.E. Dean Kennedy Institute of Rheumatology Division, Imperial College London, 65 Aspenlea Road, Hammersmith, London W6 8LH, UK Abstract: The p38 mitogen-activated protein kinase (MAPK) signaling pathway has been strongly implicated in many of the processes that underlie the pathology of rheumatoid arthritis (RA). For many years it has been considered a promising target for development of new anti-inflammatory drugs with which to treat RA and other chronic immune-mediated inflammatory diseases. However, several recent clinical trials have concluded in a disappointing manner. Why is this so, if p38 MAPK clearly contributes to the excessive production of inflammatory mediators, the destruction of bone and cartilage? We argue that, to explain the apparent failure of p38 inhibitors in the rheumatology clinic, we need to understand better the complexities of the p38 pathway and its many levels of communication with other cellular signaling pathways. In this review we look at the p38 MAPK pathway from a slightly different perspective, emphasising its role in post-transcriptional rather than transcriptional control of gene expression, and its contribution to the off-phase rather than the on-phase of the inflammatory response. Keywords: p38 MAPK, inflammatory mediators, gene expression, phosphorylation, listeria monocytogenes. ACTIVATION OF P38 MAPK play a major role in the transmission of activating signals from cell surface receptors to TAK1 [4-8]. In mammals four members of the p38 MAPK family are encoded by discrete genes.
    [Show full text]
  • Type 2 Cgmp-Dependent Protein Kinase Regulates Homeostasis by Blocking C-Jun N-Terminal Kinase in the Colon Epithelium
    Cell Death and Differentiation (2014) 21, 427–437 & 2014 Macmillan Publishers Limited All rights reserved 1350-9047/14 www.nature.com/cdd Type 2 cGMP-dependent protein kinase regulates homeostasis by blocking c-Jun N-terminal kinase in the colon epithelium R Wang1, I-K Kwon1, N Singh1, B Islam1, K Liu1, S Sridhar2, F Hofmann3 and DD Browning*,1 Analysis of knockout animals indicates that 30,50cyclic guanosine monophosphate (cGMP) has an important role in gut homeostasis but the signaling mechanism is not known. The goals of this study were to test whether increasing cGMP could affect colon homeostasis and determine the mechanism. We increased cGMP in the gut of Prkg2 þ / þ and Prkg2 À / À mice by treating with the PDE5 inhibitor Vardenafil (IP). Proliferation, differentiation and apoptosis in the colon mucosa were then quantitated. Vardenafil (Vard) treatment increased cGMP in colon mucosa of all mice, but reduced proliferation and apoptosis, and increased differentiation only in Prkg2 þ / þ mice. Vard and cGMP treatment also increased dual specificity protein phosphatase 10 (DUSP10) expression and reduced phospho-c-Jun N-terminal kinase (JNK) levels in the colon mucosa of Prkg2 þ / þ but not Prkg2 À / À mice. Treatment of Prkg2 À / À mice with the JNK inhibitor SP600125 reversed the defective homeostasis observed in these animals. Activation of protein kinase G2 (PKG2) in goblet-like LS174T cells increased DUSP10 expression and reduced JNK activity. PKG2 also increased goblet cell-specific MUC2 expression in LS174T cells, and this process was blocked by DUSP10-specific siRNA. The ability of cGMP signaling to inhibit JNK-induced apoptosis in vivo was demonstrated using dextran sodium sulfate (DSS) to stress the colon epithelium.
    [Show full text]
  • Dual Specificity Phosphatases from Molecular Mechanisms to Biological Function
    International Journal of Molecular Sciences Dual Specificity Phosphatases From Molecular Mechanisms to Biological Function Edited by Rafael Pulido and Roland Lang Printed Edition of the Special Issue Published in International Journal of Molecular Sciences www.mdpi.com/journal/ijms Dual Specificity Phosphatases Dual Specificity Phosphatases From Molecular Mechanisms to Biological Function Special Issue Editors Rafael Pulido Roland Lang MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade Special Issue Editors Rafael Pulido Roland Lang Biocruces Health Research Institute University Hospital Erlangen Spain Germany Editorial Office MDPI St. Alban-Anlage 66 4052 Basel, Switzerland This is a reprint of articles from the Special Issue published online in the open access journal International Journal of Molecular Sciences (ISSN 1422-0067) from 2018 to 2019 (available at: https: //www.mdpi.com/journal/ijms/special issues/DUSPs). For citation purposes, cite each article independently as indicated on the article page online and as indicated below: LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. Journal Name Year, Article Number, Page Range. ISBN 978-3-03921-688-8 (Pbk) ISBN 978-3-03921-689-5 (PDF) c 2019 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. The book as a whole is distributed by MDPI under the terms and conditions of the Creative Commons license CC BY-NC-ND. Contents About the Special Issue Editors ....................................
    [Show full text]
  • Revisiting the Roles of VHR/DUSP3 Phosphatase in Human Diseases
    REVIEW ARTICLE Revisiting the roles of VHR/DUSP3 phosphatase in human diseases Lilian Cristina Russo, Je´ssica Oliveira Farias, Pault Yeison Minaya Ferruzo, Lucas Falca˜o Monteiro, Fa´bio Luı´sForti* Departamento de Bioquı´mica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo, SP, BR. Russo LC, Farias JO, Ferruzo PY,Monteiro LF,Forti FL. Revisiting the roles of VHR/DUSP3 phosphatase in human diseases. Clinics. 2018;73(suppl 1):e466s *Corresponding author. E-mail: fl[email protected] Protein tyrosine phosphatases have long been considered key regulators of biological processes and are there- fore implicated in the origins of various human diseases. Heterozygosity, mutations, deletions, and the complete loss of some of these enzymes have been reported to cause neurodegenerative diseases, autoimmune syndromes, genetic disorders, metabolic diseases, cancers, and many other physiological imbalances. Vaccinia H1-related phos- phatase, also known as dual-specificity phosphatase 3, is a protein tyrosine phosphatase enzyme that regulates the phosphorylation of the mitogen-activated protein kinase signaling pathway, a central mediator of a diver- sity of biological responses. It has been suggested that vaccinia H1-related phosphatase can act as a tumor sup- pressor or tumor-promoting phosphatase in different cancers. Furthermore, emerging evidence suggests that this enzyme has many other biological functions, such as roles in immune responses, thrombosis, hemostasis, angio- genesis, and genomic stability, and this broad spectrum of vaccinia H1-related phosphatase activity is likely the result of its diversity of substrates. Hence, fully identifying and characterizing these substrate-phosphatase interactions will facilitate the identification of pharmacological inhibitors of vaccinia H1-related phosphatase that can be evaluated in clinical trials.
    [Show full text]
  • 257.Full.Pdf
    TNF-α Induces Tyrosine Phosphorylation and Recruitment of the Src Homology Protein-Tyrosine Phosphatase 2 to the gp130 Signal-Transducing Subunit of the IL-6 This information is current as Receptor Complex of October 1, 2021. Johannes G. Bode, Jens Schweigart, Jan Kehrmann, Christian Ehlting, Fred Schaper, Peter C. Heinrich and Dieter Häussinger J Immunol 2003; 171:257-266; ; Downloaded from doi: 10.4049/jimmunol.171.1.257 http://www.jimmunol.org/content/171/1/257 References This article cites 54 articles, 32 of which you can access for free at: http://www.jimmunol.org/ http://www.jimmunol.org/content/171/1/257.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on October 1, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology TNF-␣ Induces Tyrosine Phosphorylation and Recruitment of the Src Homology Protein-Tyrosine Phosphatase 2 to the gp130 Signal-Transducing Subunit of the IL-6 Receptor Complex1 Johannes G.
    [Show full text]