Inter- and Intracellular Signaling in Amyotrophic Lateral Sclerosis: Role of p38 Mitogen-Activated Protein Kinase

2005 ◽  
Vol 2 (3-4) ◽  
pp. 128-134 ◽  
Author(s):  
C. Bendotti ◽  
M. Bao Cutrona ◽  
C. Cheroni ◽  
G. Grignaschi ◽  
D. Lo Coco ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Kinase ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Lateral Sclerosis

scholarly journals Mitogen-Activated Protein Kinase Pathway in Amyotrophic Lateral Sclerosis

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 969
Author(s):  
TG Sahana ◽  
Ke Zhang
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Kinase ◽  
Mapk Pathway ◽  
Signal Transduction Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Spinal Cord Tissue ◽  
Disease Manifestation ◽  
Drug Candidates ◽  
Mitogen Activated Protein ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a fatal motor neuron degenerative disease. Multiple genetic and non-genetic risk factors are associated with disease pathogenesis, and several cellular processes, including protein homeostasis, RNA metabolism, vesicle transport, etc., are severely impaired in ALS conditions. Despite the heterogeneity of the disease manifestation and progression, ALS patients show protein aggregates in the motor cortex and spinal cord tissue, which is believed to be at least partially caused by aberrant phase separation and the formation of persistent stress granules. Consistent with this notion, many studies have implicated cellular stress, such as ER stress, DNA damage, oxidative stress, and growth factor depletion, in ALS conditions. The mitogen-activated protein kinase (MAPK) pathway is a fundamental mitogen/stress-activated signal transduction pathway that regulates cell proliferation, differentiation, survival, and death. Here we summarize the fundamental role of MAPK in physiology and ALS pathogenesis. We also discuss pharmacological inhibitors targeting this pathway tested in pre-clinical models, suggesting their role as potential drug candidates.

Stromal-derived factor 1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4142-4151 ◽  
Author(s):  
Marcin Majka ◽  
Anna Janowska-Wieczorek ◽  
Janina Ratajczak ◽  
M. Anna Kowalska ◽  
Gaston Vilaire ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Intracellular Signaling ◽  
Phosphatidyl Inositol ◽  
Mek Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Proliferative Effect ◽  
Normal Human ◽  
And Migration ◽  
Induced Apoptosis

Abstract The role of the chemokine binding stromal-derived factor 1 (SDF-1) in normal human megakaryopoiesis at the cellular and molecular levels and its comparison with that of thrombopoietin (TPO) have not been determined. In this study it was found that SDF-1, unlike TPO, does not stimulate αIIbβ3+ cell proliferation or differentiation or have an antiapoptotic effect. However, it does induce chemotaxis, trans-Matrigel migration, and secretion of matrix metalloproteinase 9 (MMP-9) and vascular endothelial growth factor (VEGF) by these cells, and both SDF-1 and TPO increase the adhesion of αIIbβ3+ cells to fibrinogen and vitronectin. Investigating the intracellular signaling pathways induced by SDF-1 and TPO revealed some overlapping patterns of protein phosphorylation/activation (mitogen-activated protein kinase [MAPK] p42/44, MAPK p38, and AKT [protein kinase B]) and some that were distinct for TPO (eg, JAK-STAT) and for SDF-1 (eg, NF-κB). It was also found that though inhibition of phosphatidyl-inositol 3-kinase (PI-3K) by LY294002 in αIIbβ3+ cells induced apoptosis and inhibited chemotaxis adhesion and the secretion of MMP-9 and VEGF, the inhibition of MAPK p42/44 (by the MEK inhibitor U0126) had no effect on the survival, proliferation, and migration of these cells. Hence, it is suggested that the proliferative effect of TPO is more related to activation of the JAK-STAT pathway (unique to TPO), and the PI-3K–AKT axis is differentially involved in TPO- and SDF-1–dependent signaling. Accordingly, PI-3K is involved in TPO-mediated inhibition of apoptosis, TPO- and SDF-1–regulated adhesion to fibrinogen and vitronectin, and SDF-1–mediated migration. This study expands the understanding of the role of SDF-1 and TPO in normal human megakaryopoiesis and indicates the molecular basis of the observed differences in cellular responses.

scholarly journals TRAF6-Dependent Mitogen-Activated Protein Kinase Activation Differentially Regulates the Production of Interleukin-12 by Macrophages in Response to Toxoplasma gondii

2004 ◽  
Vol 72 (10) ◽  
pp. 5662-5667 ◽  
Author(s):  
Nicola J. Mason ◽  
Jim Fiore ◽  
Takashi Kobayashi ◽  
Katherine S. Masek ◽  
Yongwon Choi ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Toxoplasma Gondii ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Interleukin 12 ◽  
Wild Type ◽  
Kinase Activation ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The production of interleukin-12 (IL-12) is critical to the development of innate and adaptive immune responses required for the control of intracellular pathogens. Many microbial products signal through Toll-like receptors (TLR) and activate NF-κB family members that are required for the production of IL-12. Recent studies suggest that components of the TLR pathway are required for the production of IL-12 in response to the parasite Toxoplasma gondii; however, the production of IL-12 in response to this parasite is independent of NF-κB activation. The adaptor molecule TRAF6 is involved in TLR signaling pathways and associates with serine/threonine kinases involved in the activation of both NF-κB and mitogen-activated protein kinase (MAPK). To elucidate the intracellular signaling pathways involved in the production of IL-12 in response to soluble toxoplasma antigen (STAg), wild-type and TRAF6−/− mice were inoculated with STAg, and the production of IL-12(p40) was determined. TRAF6−/− mice failed to produce IL-12(p40) in response to STAg, and TRAF6−/− macrophages stimulated with STAg also failed to produce IL-12(p40). Studies using Western blot analysis of wild-type and TRAF6−/− macrophages revealed that stimulation with STAg resulted in the rapid TRAF6-dependent phosphorylation of p38 and extracellular signal-related kinase, which differentially regulated the production of IL-12(p40). The studies presented here demonstrate for the first time that the production of IL-12(p40) in response to toxoplasma is dependent upon TRAF6 and p38 MAPK.

Role of p38 Mitogen-Activated Protein Kinase in Thrombus Formation

2004 ◽  
Vol 24 (4) ◽  
pp. 283-296 ◽  
Author(s):  
Kanako Sakurai ◽  
Yuji Matsuo ◽  
Tatsuhiko Sudo ◽  
Yoh Takuwa ◽  
Sadao Kimura ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Thrombus Formation ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein

scholarly journals Dual-mode regulation of the APC/C by CDK1 and MAPK controls meiosis I progression and fidelity

2014 ◽  
Vol 204 (6) ◽  
pp. 891-900 ◽  
Author(s):  
Ibtissem Nabti ◽  
Petros Marangos ◽  
Jenny Bormann ◽  
Nobuaki R. Kudo ◽  
John Carroll
Keyword(s):  
Protein Kinase ◽  
Spindle Assembly Checkpoint ◽  
Mitogen Activated Protein Kinase ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Female Meiosis ◽  
Dual Mode ◽  
Mitogen Activated Protein ◽  
Meiosis I

Female meiosis is driven by the activities of two major kinases, cyclin-dependent kinase 1 (Cdk1) and mitogen-activated protein kinase (MAPK). To date, the role of MAPK in control of meiosis is thought to be restricted to maintaining metaphase II arrest through stabilizing Cdk1 activity. In this paper, we find that MAPK and Cdk1 play compensatory roles to suppress the anaphase-promoting complex/cyclosome (APC/C) activity early in prometaphase, thereby allowing accumulation of APC/C substrates essential for meiosis I. Furthermore, inhibition of MAPK around the onset of APC/C activity at the transition from meiosis I to meiosis II led to accelerated completion of meiosis I and an increase in aneuploidy at metaphase II. These effects appear to be mediated via a Cdk1/MAPK-dependent stabilization of the spindle assembly checkpoint, which when inhibited leads to increased APC/C activity. These findings demonstrate new roles for MAPK in the regulation of meiosis in mammalian oocytes.

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