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 Epithelial Adhesion Mediated by Pilin SpaC Is Required for Lactobacillus rhamnosus GG-Induced Cellular Responses

2014 ◽  
Vol 80 (16) ◽  
pp. 5068-5077 ◽  
Author(s):  
Courtney S. Ardita ◽  
Jeffrey W. Mercante ◽  
Young Man Kwon ◽  
Liping Luo ◽  
Madelyn E. Crawford ◽  
...  
Keyword(s):  
Lactobacillus Rhamnosus ◽  
Surface Protein ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Critical Surface ◽  
Content Type ◽  
Epithelial Migration ◽  
Extracellular Signal ◽  
Nadph Oxidase 1 ◽  
Mitogen Activated Protein

ABSTRACTLactobacillus rhamnosusGG is a widely used probiotic, and the strain's salutary effects on the intestine have been extensively documented. We previously reported that strain GG can modulate inflammatory signaling, as well as epithelial migration and proliferation, by activating NADPH oxidase 1-catalyzed generation of reactive oxygen species (ROS). However, how strain GG induces these responses is unknown. Here, we report that strain GG's probiotic benefits are dependent on the bacterial-epithelial interaction mediated by the SpaC pilin subunit. By comparing strain GG to an isogenic mutant that lacks SpaC (strain GGΩspaC), we establish that SpaC is necessary for strain GG to adhere to gut mucosa, that SpaC contributes to strain GG-induced epithelial generation of ROS, and that SpaC plays a role in strain GG's capacity to stimulate extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling in enterocytes. In addition, we show that SpaC is required for strain GG-mediated stimulation of cell proliferation and protection against radiologically inflicted intestinal injury. The identification of a critical surface protein required for strain GG to mediate its probiotic influence advances our understanding of the molecular basis for the symbiotic relationship between some commensal bacteria of the gut lumen and enterocytes. Further insights into this relationship are critical for the development of novel approaches to treat intestinal diseases.

scholarly journals RACK1 Targets the Extracellular Signal-Regulated Kinase/Mitogen-Activated Protein Kinase Pathway To Link Integrin Engagement with Focal Adhesion Disassembly and Cell Motility

2007 ◽  
Vol 27 (23) ◽  
pp. 8296-8305 ◽  
Author(s):  
Tomas Vomastek ◽  
Marcin P. Iwanicki ◽  
Hans-Joerg Schaeffer ◽  
Adel Tarcsafalvi ◽  
J. Thomas Parsons ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Focal Adhesion ◽  
Focal Adhesions ◽  
Mitogen Activated Protein Kinase ◽  
Erk Pathway ◽  
Large Measure ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Erk Activity

ABSTRACT The extracellular signal-regulated kinase (ERK) cascade is activated in response to a multitude of extracellular signals and converts these signals into a variety of specific biological responses, including cell differentiation, cell movement, cell division, and apoptosis. The specificity of the biological response is likely to be controlled in large measure by the localization of signaling, thus enabling ERK activity to be directed towards specific targets. Here we show that the RACK1 scaffold protein functions specifically in integrin-mediated activation of the mitogen-activated protein kinase/ERK cascade and targets active ERK to focal adhesions. We found that RACK1 associated with the core kinases of the ERK pathway, Raf, MEK, and ERK, and that attenuation of RACK1 expression resulted in a decrease in ERK activity in response to adhesion but not in response to growth factors. RACK1 silencing also caused a reduction of active ERK in focal adhesions, an increase in focal adhesion length, a decreased rate of focal adhesion disassembly, and decreased motility. Our data further suggest that focal adhesion kinase is an upstream activator of the RACK1/ERK pathway. We suggest that RACK1 tethers the ERK pathway core kinases and channels signals from upstream activation by integrins to downstream targets at focal adhesions.

scholarly journals Phosphorylation of Msx1 promotes cell proliferation through the Fgf9/18-MAPK signaling pathway during embryonic limb development

2020 ◽  
Vol 48 (20) ◽  
pp. 11452-11467
Author(s):  
Yenan Yang ◽  
Xiaoli Zhu ◽  
Xiang Jia ◽  
Wanwan Hou ◽  
Guoqiang Zhou ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Limb Development ◽  
Early Stage ◽  
Control Cell ◽  
Cell Lineage ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Embryonic Limb ◽  
Underlying Mechanisms

Abstract Msh homeobox (Msx) is a subclass of homeobox transcriptional regulators that control cell lineage development, including the early stage of vertebrate limb development, although the underlying mechanisms are not clear. Here, we demonstrate that Msx1 promotes the proliferation of myoblasts and mesenchymal stem cells (MSCs) by enhancing mitogen-activated protein kinase (MAPK) signaling. Msx1 directly binds to and upregulates the expression of fibroblast growth factor 9 (Fgf9) and Fgf18. Accordingly, knockdown or antibody neutralization of Fgf9/18 inhibits Msx1-activated extracellular signal-regulated kinase 1/2 (Erk1/2) phosphorylation. Mechanistically, we determined that the phosphorylation of Msx1 at Ser136 is critical for enhancing Fgf9 and Fgf18 expression and cell proliferation, and cyclin-dependent kinase 1 (CDK1) is apparently responsible for Ser136 phosphorylation. Furthermore, mesenchymal deletion of Msx1/2 results in decreased Fgf9 and Fgf18 expression and Erk1/2 phosphorylation, which leads to serious defects in limb development in mice. Collectively, our findings established an important function of the Msx1-Fgf-MAPK signaling axis in promoting cell proliferation, thus providing a new mechanistic insight into limb development.

scholarly journals Transcriptomic and Network Analysis Identifies Shared and Unique Pathways across Dementia Spectrum Disorders

2020 ◽  
Vol 21 (6) ◽  
pp. 2050 ◽  
Author(s):  
Jose A. Santiago ◽  
Virginie Bottero ◽  
Judith A. Potashkin
Keyword(s):  
Transcription Factors ◽  
Protein Kinase ◽  
Mapk Signaling ◽  
Pentose Phosphate ◽  
Mitogen Activated Protein Kinase ◽  
Health Concern ◽  
Mitogen Activated Protein ◽  
Common Etiology ◽  
Nuclear Factor Kappa Beta ◽  
Upregulated Genes

Background: Dementia is a growing public health concern with an estimated prevalence of 50 million people worldwide. Alzheimer’s disease (AD) and vascular and frontotemporal dementias (VaD, FTD), share many clinical, genetical, and pathological features making the diagnosis difficult. Methods: In this study, we compared the transcriptome from the frontal cortex of patients with AD, VaD, and FTD to identify dysregulated pathways. Results: Upregulated genes in AD were enriched in adherens and tight junctions, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase and protein kinase B/Akt signaling pathways, whereas downregulated genes associated with calcium signaling. Upregulated genes in VaD were centered on infectious diseases and nuclear factor kappa beta signaling, whereas downregulated genes are involved in biosynthesis of amino acids and the pentose phosphate pathway. Upregulated genes in FTD were associated with ECM receptor interactions and the lysosome, whereas downregulated genes were involved in glutamatergic synapse and MAPK signaling. The transcription factor KFL4 was shared among the 3 types of dementia. Conclusions: Collectively, we identified similarities and differences in dysregulated pathways and transcription factors among the dementias. The shared pathways and transcription factors may indicate a potential common etiology, whereas the differences may be useful for distinguishing dementias.

scholarly journals Praeruptorin B Mitigates the Metastatic Ability of Human Renal Carcinoma Cells through Targeting CTSC and CTSV Expression

2020 ◽  
Vol 21 (8) ◽  
pp. 2919
Author(s):  
Chia-Liang Lin ◽  
Tung-Wei Hung ◽  
Tsung-Ho Ying ◽  
Chi-Jui Lin ◽  
Yi-Hsien Hsieh ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Cellular Migration ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Antitumor Effects ◽  
Protein Levels ◽  
Extracellular Signal ◽  
Adult Kidney ◽  
Mitogen Activated Protein ◽  
Underlying Mechanisms

Renal cell carcinoma (RCC) is the most common adult kidney cancer, and accounts for 85% of all cases of kidney cancers worldwide. Praeruptorin B (Pra-B) is a bioactive constituent of Peucedanum praeruptorum Dunn and exhibits several pharmacological activities, including potent antitumor effects. However, the anti-RCC effects of Pra-B and their underlying mechanisms are unclear; therefore, we explored the effects of Pra-B on RCC cells in this study. We found that Pra-B nonsignificantly influenced the cell viability of human RCC cell lines 786-O and ACHN at a dose of less than 30 μM for 24 h treatment. Further study revealed that Pra-B potently inhibited the migration and invasion of 786-O and ACHN cells, as well as downregulated the mRNA and protein expression of cathepsin C (CTSC) and cathepsin V (CTSV) of 786-O and ACHN cells. Mechanistically, Pra-B also reduced the protein levels of phospho (p)-epidermal growth factor receptor (EGFR), p-mitogen-activated protein kinase kinase (MEK), and p-extracellular signal-regulated kinases (ERK) in RCC cells. In addition, Pra-B treatment inhibited the effect of EGF on the upregulation of EGFR–MEK–ERK, CTSC and CTSV expression, cellular migration, and invasion of 786-O cells. Our findings are the first to demonstrate that Pra-B can reduce the migration and invasion ability of human RCC cells through suppressing the EGFR-MEK-ERK signaling pathway and subsequently downregulating CTSC and CTSV. This evidence suggests that Pra-B can be developed as an effective antimetastatic agent for the treatment of RCC.

scholarly journals Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

2004 ◽  
Vol 24 (3) ◽  
pp. 1081-1095 ◽  
Author(s):  
Nicole H. Purcell ◽  
Dina Darwis ◽  
Orlando F. Bueno ◽  
Judith M. Müller ◽  
Roland Schüle ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Interacting Protein ◽  
Hypertrophic Response ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

scholarly journals Role of Mitogen-Activated Protein Kinases in Peptidoglycan-Induced Expression of Inducible Nitric Oxide Synthase and Nitric Oxide in Mouse Peritoneal Macrophages: Extracellular Signal-Related Kinase, a Negative Regulator

2011 ◽  
Vol 18 (6) ◽  
pp. 994-1001 ◽  
Author(s):  
Kunal H. Bhatt ◽  
Ajit Sodhi ◽  
Rituparna Chakraborty
Keyword(s):  
Nitric Oxide ◽  
Transcription Factors ◽  
Inos Expression ◽  
No Production ◽  
Erk Pathway ◽  
Mitogen Activated Protein Kinases ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Oxide Synthase ◽  
Inducible Nitric Oxide

ABSTRACTThe expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) are important host defense mechanisms against pathogens in mononuclear phagocytes. The objectives of this study were to examine the roles of mitogen-activated protein kinases (MAPKs) and transcription factors (nuclear factor-κB [NF-κB] and activating protein 1 [AP-1]) in peptidoglycan (PGN)-induced iNOS expression and NO production in macrophages. PGN is a cell wall component of Gram-positive bacteria that stimulates inflammatory responses bothex vivoandin vivo. PGN stimulates the activation of all three classes of MAPKs, extracellular signal-related kinase (ERK), c-Jun N-terminal kinase (JNK), and p38mapkin macrophages, albeit with differential activation kinetics. Using a selective inhibitor of JNK (SP600125) and JNK1/2 small interfering RNA (siRNA) knocked-down macrophages, it was observed that PGN-induced iNOS and NO expression is significantly inhibited. This suggested that JNK MAPK plays an essential role in PGN-induced iNOS expression and NO production. In contrast, inhibition of the ERK pathway using PD98059 dose dependently enhanced PGN-induced iNOS expression and NO production. PGN-induced ERK activation was attenuated in ERK1/2 siRNA knocked-down macrophages; however, NO and iNOS expression were significantly enhanced. An electrophoretic mobility shift assay showed that SP600125 inhibited PGN-induced NF-κB and AP-1 activation, whereas inhibition of the ERK pathway enhanced NF-κB activation, but with no effect on AP-1. These results indicate that the JNK MAPK positively regulate PGN-induced iNOS and NO expression by activating NF-κB and AP-1 transcription factors, whereas the ERK pathway plays a negative regulatory role via affecting NF-κB activity.

scholarly journals ERK2 phosphorylates the epigenetic regulator CXXC-finger protein 1 (CFP1)

2019 ◽  
Author(s):  
Aroon S. Karra ◽  
Aileen M. Klein ◽  
Svetlana Earnest ◽  
Steve Stippec ◽  
Chonlarat Wichaidit ◽  
...  
Keyword(s):  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Early Gene ◽  
Highly Active ◽  
Finger Protein ◽  
Extracellular Signal ◽  
Epigenetic Regulator ◽  
Mitogen Activated Protein ◽  
Cxxc Finger Protein 1

AbstractBackgroundThe Ras-Raf-MEK-ERK signaling pathway is essential for proper development and homeostatic regulation in eukaryotic cells and underlies progression of several types of cancer. Many pathway functions are performed by extracellular signal-regulated kinase (ERK)1 and 2 (ERK1/2), serine/threonine protein kinases of the mitogen-activated protein kinase (MAPK) family that interact with a large number of substrates and are highly active in the nucleus.ResultsWe identified the epigenetic regulator CXXC-finger protein 1 (CFP1) as a protein that interacts with ERK2 on chromatin. CFP1 is involved in multiple aspects of chromatin regulation, including histone methylation and DNA methylation. Here, we demonstrate the overlapping roles for ERK1/2 and CFP1 in regulation of immediate early gene (IEG) induction. Our work suggests multiple modes of co-regulation and demonstrates that CFP1 is required for an optimal signal-dependent response. We also show that CFP1 is an ERK2 substrate in vitro and identify several phosphorylation sites. Furthermore, we provide evidence that Su(var)3-9, Enhancer-of-zeste and Trithorax (Set)1b, a CFP1-interacting histone methylase, is phosphorylated by ERK2 and is regulated by CFP1.ConclusionOur work highlights ERK1/2 interactions with chromatin regulators that contribute to MAPK signaling diversity in the nucleus.

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