scholarly journals Dual-Specificity Phosphatase Regulation in Neurons and Glial Cells

2019 ◽  
Vol 20 (8) ◽  
pp. 1999 ◽  
Author(s):  
Pérez-Sen ◽  
Queipo ◽  
Gil-Redondo ◽  
Ortega ◽  
Gómez-Villafuertes ◽  
...  
Keyword(s):  
Map Kinases ◽  
Protein Phosphatases ◽  
Mapk Signaling ◽  
Protein Stabilization ◽  
Mitogen Activated Protein Kinase ◽  
Brain Diseases ◽  
General Terms ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Specificity Protein

Dual-specificity protein phosphatases comprise a protein phosphatase subfamily with selectivity towards mitogen-activated protein (MAP) kinases, also named MKPs, or mitogen-activated protein kinase (MAPK) phosphatases. As powerful regulators of the intensity and duration of MAPK signaling, a relevant role is envisioned for dual-specificity protein phosphatases (DUSPs) in the regulation of biological processes in the nervous system, such as differentiation, synaptic plasticity, and survival. Important neural mediators include nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) that contribute to DUSP transcriptional induction and post-translational mechanisms of DUSP protein stabilization to maintain neuronal survival and differentiation. Potent DUSP gene inducers also include cannabinoids, which preserve DUSP activity in inflammatory conditions. Additionally, nucleotides activating P2X7 and P2Y13 nucleotide receptors behave as novel players in the regulation of DUSP function. They increase cell survival in stressful conditions, regulating DUSP protein turnover and inducing DUSP gene expression. In general terms, in the context of neural cells exposed to damaging conditions, the recovery of DUSP activity is neuroprotective and counteracts pro-apoptotic over-activation of p38 and JNK. In addition, remarkable changes in DUSP function take place during the onset of neuropathologies. The restoration of proper DUSP levels and recovery of MAPK homeostasis underlie the therapeutic effect, indicating that DUSPs can be relevant targets for brain diseases.

scholarly journals JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection

2019 ◽  
Vol 20 (19) ◽  
pp. 4779 ◽  
Author(s):  
Jeanne K. DuShane ◽  
Colleen L. Mayberry ◽  
Michael P. Wilczek ◽  
Sarah L. Nichols ◽  
Melissa S. Maginnis
Keyword(s):  
Transcription Factors ◽  
Mapk Signaling ◽  
Mapk Cascade ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Downstream Signaling ◽  
Dual Specificity ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Underlying Mechanisms

JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.

scholarly journals Expression, purification and characterization of recombinant mitogen-activated protein kinase kinases

1994 ◽  
Vol 303 (1) ◽  
pp. 105-112 ◽  
Author(s):  
P Dent ◽  
Y H Chow ◽  
J Wu ◽  
D K Morrison ◽  
R Jove ◽  
...  
Keyword(s):  
Peptide Mapping ◽  
Mitogen Activated Protein Kinase ◽  
Recombinant Viruses ◽  
Dual Specificity ◽  
Protein Map ◽  
Mitogen Activated Protein ◽  
Michaelis Constants ◽  
High Level ◽  
Specificity Protein

Mitogen-activated protein (MAP) kinase kinases (MKKs) are dual-specificity protein kinases which activate p42mapk and p44mapk by phosphorylation of regulatory tyrosine and threonine residues. cDNAs for two isotypes of MKK, MKK1 and MKK2, have been isolated from several species. Here we describe construction of recombinant baculoviruses for high-level expression of histidine-tagged rat MKK1 and MKK2, and procedures for production of nearly homogeneous MKK1 and MKK2 fusion proteins, in both inactive and active forms. Co-infection of Sf9 cells with either MKK1 or MKK2 virus together with recombinant viruses for Raf-1, pp60src (Y527F) and c-Ha-Ras resulted in activations of 250-fold and 150-fold for MKK1 and MKK2 respectively. Specific activities towards kinase-defective p42mapk were of the order of several hundred nanomoles of phosphate transferred/min per mg of MKK protein. The Michaelis constants for both enzymes were approx. 1 microM. Preparations of activated MKK were apparently free of Raf-1 as assessed by Western blotting. Raf-1 phosphorylated MKK1 on one major tryptic phosphopeptide, the phosphorylation of which increased with time. This phosphopeptide contained only phosphoserine and possessed neutral overall charge at pH 1.9 on two-dimensional peptide mapping. Phosphorylation of MKK1 by Raf-1 correlated with activation and reached a plateau of approximately 2 mol/mol.

scholarly journals Mitogen-Activated Protein Kinase Phosphatases (MKPs) in Fungal Signaling: Conservation, Function, and Regulation

2019 ◽  
Vol 20 (7) ◽  
pp. 1709 ◽  
Author(s):  
Gema González-Rubio ◽  
Teresa Fernández-Acero ◽  
Humberto Martín ◽  
María Molina
Keyword(s):  
Rna Binding ◽  
Rna Binding Proteins ◽  
Specific Interaction ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cell Physiology ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Activation Mechanisms ◽  
Dual Specificity Phosphatases

Mitogen-activated protein kinases (MAPKs) are key mediators of signaling in fungi, participating in the response to diverse stresses and in developmental processes. Since the precise regulation of MAPKs is fundamental for cell physiology, fungi bear dual specificity phosphatases (DUSPs) that act as MAP kinase phosphatases (MKPs). Whereas fungal MKPs share characteristic domains of this phosphatase subfamily, they also have specific interaction motifs and particular activation mechanisms, which, for example, allow some yeast MKPs, such as Saccharomyces cerevisiae Sdp1, to couple oxidative stress with substrate recognition. Model yeasts show that MKPs play a key role in the modulation of MAPK signaling flow. Mutants affected in S. cerevisiae Msg5 or in Schizosaccharomyces pombe Pmp1 display MAPK hyperactivation and specific phenotypes. MKPs from virulent fungi, such as Candida albicans Cpp1, Fusarium graminearum Msg5, and Pyricularia oryzae Pmp1, are relevant for pathogenicity. Apart from transcriptional regulation, MKPs can be post-transcriptionally regulated by RNA-binding proteins such as Rnc1, which stabilizes the S. pombe PMP1 mRNA. P. oryzae Pmp1 activity and S. cerevisiae Msg5 stability are regulated by phosphorylation and ubiquitination, respectively. Therefore, fungi offer a platform to gain insight into the regulatory mechanisms that control MKPs.

Engagement of CD11b and CD11c β2 integrin by antibodies or soluble CD23 induces IL-1β production on primary human monocytes through mitogen-activated protein kinase–dependent pathways

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3868-3877 ◽  
Author(s):  
Roger Rezzonico ◽  
Rachel Chicheportiche ◽  
Veronique Imbert ◽  
Jean-Michel Dayer
Keyword(s):  
Protein Kinase ◽  
Messenger Rna ◽  
Transcriptional Control ◽  
Map Kinases ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Transcriptional Level ◽  
Mitogen Activated Protein ◽  
Dose Dependent Fashion ◽  
Β2 Integrins

β2 integrins are involved in the recruitment of leukocytes to inflammatory sites and in cellular activation. We demonstrate that ligation of CD11b (Mac-1, CR3) or CD11c (p150, CR4) alpha chains of β2 integrins by mAbs or soluble chimeric CD23 (sCD23) on human freshly isolated monocytes rapidly stimulates high levels of interleukin-1β production. This induction takes place at the transcriptional level and is regulated by members of the mitogen-activated protein kinase (MAPK) family. Indeed, stimulation of monocytes through engagement of CD11b or CD11c results in the phosphorylation and activation of ERK1, ERK2, and p38/SAPK2 MAP kinases. U0126, a potent inhibitor of the upstream activator of ERK1/2, ie, MEK1/2, suppresses IL-1β messenger RNA (mRNA) expression in a dose-dependent fashion, showing the implication of this pathway in the transcriptional control of IL-1β production. On the other hand, inhibition of p38 by SB203580 indicates that this MAPK is involved in the control of IL-1β production at both transcriptional and translational levels. Together these data demonstrate that ligation of CD11b and CD11c β2 integrins by mAbs or sCD23 fusion proteins triggers the activation of 2 distinct MAPK signaling pathways that cooperate in controlling IL-1β synthesis at different levels.

Engagement of CD11b and CD11c β2 integrin by antibodies or soluble CD23 induces IL-1β production on primary human monocytes through mitogen-activated protein kinase–dependent pathways

Blood ◽  
2000 ◽  
Vol 95 (12) ◽  
pp. 3868-3877 ◽  
Author(s):  
Roger Rezzonico ◽  
Rachel Chicheportiche ◽  
Veronique Imbert ◽  
Jean-Michel Dayer
Keyword(s):  
Protein Kinase ◽  
Messenger Rna ◽  
Transcriptional Control ◽  
Map Kinases ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Transcriptional Level ◽  
Mitogen Activated Protein ◽  
Dose Dependent Fashion ◽  
Β2 Integrins

Abstract β2 integrins are involved in the recruitment of leukocytes to inflammatory sites and in cellular activation. We demonstrate that ligation of CD11b (Mac-1, CR3) or CD11c (p150, CR4) alpha chains of β2 integrins by mAbs or soluble chimeric CD23 (sCD23) on human freshly isolated monocytes rapidly stimulates high levels of interleukin-1β production. This induction takes place at the transcriptional level and is regulated by members of the mitogen-activated protein kinase (MAPK) family. Indeed, stimulation of monocytes through engagement of CD11b or CD11c results in the phosphorylation and activation of ERK1, ERK2, and p38/SAPK2 MAP kinases. U0126, a potent inhibitor of the upstream activator of ERK1/2, ie, MEK1/2, suppresses IL-1β messenger RNA (mRNA) expression in a dose-dependent fashion, showing the implication of this pathway in the transcriptional control of IL-1β production. On the other hand, inhibition of p38 by SB203580 indicates that this MAPK is involved in the control of IL-1β production at both transcriptional and translational levels. Together these data demonstrate that ligation of CD11b and CD11c β2 integrins by mAbs or sCD23 fusion proteins triggers the activation of 2 distinct MAPK signaling pathways that cooperate in controlling IL-1β synthesis at different levels.

scholarly journals Rewiring MAP kinases in Saccharomyces cerevisiae to regulate novel targets through ubiquitination

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Benjamin Groves ◽  
Arjun Khakhar ◽  
Cory M Nadel ◽  
Richard G Gardner ◽  
Georg Seelig
Keyword(s):  
Map Kinases ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Kinase Substrate ◽  
Downstream Effector ◽  
Mitogen Activated Protein ◽  
Interaction Domains ◽  
Novel Targets ◽  
Kinase Pathway ◽  
Insight Into

Evolution has often copied and repurposed the mitogen-activated protein kinase (MAPK) signaling module. Understanding how connections form during evolution, in disease and across individuals requires knowledge of the basic tenets that govern kinase-substrate interactions. We identify criteria sufficient for establishing regulatory links between a MAPK and a non-native substrate. The yeast MAPK Fus3 and human MAPK ERK2 can be functionally redirected if only two conditions are met: the kinase and substrate contain matching interaction domains and the substrate includes a phospho-motif that can be phosphorylated by the kinase and recruit a downstream effector. We used a panel of interaction domains and phosphorylation-activated degradation motifs to demonstrate modular and scalable retargeting. We applied our approach to reshape the signaling behavior of an existing kinase pathway. Together, our results demonstrate that a MAPK can be largely defined by its interaction domains and compatible phospho-motifs and provide insight into how MAPK-substrate connections form.

scholarly journals Structure ofMycobacterium smegmatisEis in complex with paromomycin

2014 ◽  
Vol 70 (9) ◽  
pp. 1173-1179 ◽  
Author(s):  
Kyoung Hoon Kim ◽  
Doo Ri An ◽  
Hye Jin Yoon ◽  
Jin Kuk Yang ◽  
Se Won Suh
Keyword(s):  
Crystal Structure ◽  
Aminoglycoside Antibiotic ◽  
Intracellular Survival ◽  
Mitogen Activated Protein Kinase ◽  
Host Immune Responses ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Dual Specificity Protein Phosphatase ◽  
High Level ◽  
Specificity Protein

TheRv2416cgene ofMycobacterium tuberculosis(Mtb) encodes the enhanced intracellular survival (Eis) protein that enhances intracellular survival of the pathogen in host macrophages during infection. TheMtbEis protein is released into the cytoplasm of the phagocyte during intracellular infection and modulates the host immune response. It also contributes to drug resistance by acetylating multiple amine groups of aminoglycosides. Interestingly, the nonpathogenicM. smegmatis(Msm) contains a homologouseisgene (MSMEG_3513). The overall structures ofMtbEis andMsmEis are highly similar to each other, reflecting the high level (58%) of amino-acid sequence identity between them. BothMtbEis andMsmEis are active as aminoglycoside acetyltransferases, while onlyMtbEis functions as anN∊-acetyltransferase to acetylate Lys55 of dual-specificity protein phosphatase 16 (DUSP16)/mitogen-activated protein kinase phosphatase 7 (MKP-7), leading to the suppression of host immune responses. Here, the crystal structure ofMsmEis in the paromomycin-bound form is reported, revealing detailed interactions between an aminoglycoside antibiotic andMsmEis. The crystal structure ofMsmEis in the paromomycin-bound form has been determined at 3.3 Å resolution. This work provides potentially useful information for structure-guided discovery of Eis inhibitors as a novel antituberculosis drug against drug-resistantMtb.

scholarly journals Recurrent Somatic MAP2K1 Mutations in Papillary Thyroid Cancer and Colorectal Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Rong Bu ◽  
Abdul K. Siraj ◽  
Tariq Masoodi ◽  
Sandeep Kumar Parvathareddy ◽  
Kaleem Iqbal ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Thyroid Cancer ◽  
Protein Kinase ◽  
Papillary Thyroid Cancer ◽  
Middle Eastern ◽  
Mitogen Activated Protein Kinase ◽  
Papillary Thyroid ◽  
Dual Specificity ◽  
Mitogen Activated Protein ◽  
Specificity Protein

Mitogen-activated protein kinase kinase 1 (MAP2K1) is a dual specificity protein kinase that phosphorylates both threonine and tyrosine residues in ERK. MAP2K1 mutations have been identified in several cancers. However, their role in Middle Eastern papillary thyroid cancer (PTC) and colorectal cancer (CRC) is lacking. In this study, we evaluated the prevalence of MAP2K1 mutations in a large cohort of Middle Eastern PTC and CRC using whole-exome and Sanger sequencing technology. In the discovery cohort of 100 PTC and 100 CRC cases (comprising 50 MAPK mutant and 50 MAPK wildtype cases each), we found one MAP2K1 mutation each in PTC and CRC, both of which were MAPK wildtype. We further analyzed 286 PTC and 289 CRC MAPK wildtype cases and found three MAP2K1 mutant PTC cases and two MAP2K1 mutant CRC cases. Thus, the overall prevalence of MAP2K1 mutation in MAPK wildtype cases was 1.1% (4/336) in PTC and 0.9% (3/339) in CRC. Histopathologically, three of the four MAP2K1 mutant PTC cases were follicular variant and all four tumors were unifocal with absence of extra-thyroidal extension. All the three CRC cases harboring MAP2K1 mutation were of older age (> 50 years) and had moderately differentiated stage II/III tumors located in the left colon. In conclusion, this is the first comprehensive report of MAP2K1 somatic mutations prevalence in PTC and CRC from this ethnicity. The mutually exclusive nature of MAP2K1 and MAPK mutations suggests that each of these mutation may function as an initiating mutation driving tumorigenesis through MAPK signaling pathway.

scholarly journals Atf1 Is a Target of the Mitogen-activated Protein Kinase Pmk1 and Regulates Cell Integrity in Fission Yeast

2007 ◽  
Vol 18 (12) ◽  
pp. 4794-4802 ◽  
Author(s):  
Hirofumi Takada ◽  
Masayuki Nishimura ◽  
Yuta Asayama ◽  
Yoshiaki Mannse ◽  
Shunji Ishiwata ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Fission Yeast ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Mrna Levels ◽  
Cell Integrity ◽  
Dual Specificity ◽  
Mitogen Activated Protein

In fission yeast, knockout of the calcineurin gene resulted in hypersensitivity to Cl−, and the overexpression of pmp1+ encoding a dual-specificity phosphatase for Pmk1 mitogen-activated protein kinase (MAPK) or the knockout of the components of the Pmk1 pathway complemented the Cl− hypersensitivity of calcineurin deletion. Here, we showed that the overexpression of ptc1+ and ptc3+, both encoding type 2C protein phosphatase (PP2C), previously known to inactivate the Wis1–Spc1–Atf1 stress-activated MAPK signaling pathway, suppressed the Cl− hypersensitivity of calcineurin deletion. We also demonstrated that the mRNA levels of these two PP2Cs and pyp2+, another negative regulator of Spc1, are dependent on Pmk1. Notably, the deletion of Atf1, but not that of Spc1, displayed hypersensitivity to the cell wall-damaging agents and also suppressed the Cl− hypersensitivity of calcineurin deletion, both of which are characteristic phenotypes shared by the mutation of the components of the Pmk1 MAPK pathway. Moreover, micafungin treatment induced Pmk1 hyperactivation that resulted in Atf1 hyperphosphorylation. Together, our results suggest that PP2C is involved in a negative feedback loop of the Pmk1 signaling, and results also demonstrate that Atf1 is a key component of the cell integrity signaling downstream of Pmk1 MAPK.

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