scholarly journals Thrombomodulin Regulation of Mitogen-Activated Protein Kinases

2019 ◽  
Vol 20 (8) ◽  
pp. 1851 ◽  
Author(s):  
Hemant Giri ◽  
Xiaofeng Cai ◽  
Sumith R. Panicker ◽  
Indranil Biswas ◽  
Alireza R. Rezaie
Keyword(s):  
Protein Kinases ◽  
Intracellular Signaling ◽  
Vascular Endothelial Cells ◽  
Coagulation Factors ◽  
Regulatory Relationship ◽  
Signaling Mechanism ◽  
Mitogen Activated Protein Kinases ◽  
Inflammatory Conditions ◽  
Mitogen Activated Protein ◽  
Protective Signaling

The multifaceted role of mitogen-activated protein kinases (MAPKs) in modulating signal transduction pathways in inflammatory conditions such as infection, cardiovascular disease, and cancer has been well established. Recently, coagulation factors have also emerged as key players in regulating intracellular signaling pathways during inflammation. Among coagulation factors, thrombomodulin, as a high affinity receptor for thrombin on vascular endothelial cells, has been discovered to be a potent anti-inflammatory and anti-tumorigenic signaling molecule. The protective signaling function of thrombomodulin is separate from its well-recognized role in the clotting cascade, which is to function as an anti-coagulant receptor in order to switch the specificity of thrombin from a procoagulant to an anti-coagulant protease. The underlying protective signaling mechanism of thrombomodulin remains largely unknown, though a few published reports link the receptor to the regulation of MAPKs under different (patho)physiological conditions. The goal of this review is to summarize what is known about the regulatory relationship between thrombomodulin and MAPKs.

scholarly journals Vigilant Keratinocytes Trigger Pathogen-Associated Molecular Pattern Signaling in Response to Streptococcal M1 Protein

2015 ◽  
Vol 83 (12) ◽  
pp. 4673-4681 ◽  
Author(s):  
Sandra T. Persson ◽  
Laura Wilk ◽  
Matthias Mörgelin ◽  
Heiko Herwald
Keyword(s):  
Protein Kinases ◽  
Inflammatory Mediators ◽  
Intracellular Signaling ◽  
Protective Mechanism ◽  
Mitogen Activated Protein Kinases ◽  
M1 Protein ◽  
Molecular Pattern ◽  
Superficial Skin ◽  
Mitogen Activated Protein ◽  
Pathogen Associated Molecular Pattern

The human skin exerts many functions in order to maintain its barrier integrity and protect the host from invading microorganisms. One such pathogen isStreptococcus pyogenes, which can cause a variety of superficial skin wounds that may eventually progress into invasive deep soft tissue infections. Here we show that keratinocytes recognize soluble M1 protein, a streptococcal virulence factor, as a pathogen-associated molecular pattern to release alarming inflammatory responses. We found that this interaction initiates an inflammatory intracellular signaling cascade involving the activation of the mitogen-activated protein kinases extracellular signal-regulated kinase (ERK), p38, and Jun N-terminal protein kinase and the subsequent induction and mobilization of the transcription factors NF-κB and AP-1. We also determined the imprint of the inflammatory mediators released, such as interleukin-8 (IL-8), growth-related oncogene alpha, migration inhibitory factor, extracellular matrix metalloproteinase inducer, IL-1α, IL-1 receptor a, and ST2, in response to streptococcal M1 protein. The expression of IL-8 is dependent on Toll-like receptor 2 activity and subsequent activation of the mitogen-activated protein kinases ERK and p38. Notably, this signaling seems to be distinct for IL-8 release, and it is not shared with the other inflammatory mediators. We conclude that keratinocytes participate in a proinflammatory manner in streptococcal pattern recognition and that expression of the chemoattractant IL-8 by keratinocytes constitutes an important protective mechanism against streptococcal M1 protein.

scholarly journals Activation of mitogen-activated protein kinases by a splice variant of GHRH receptor

2009 ◽  
Vol 44 (2) ◽  
pp. 127-134 ◽  
Author(s):  
Nektarios Barabutis ◽  
Agnieszka Siejka ◽  
Andrew V Schally ◽  
Norman L Block ◽  
Renzhi Cai ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Protein Kinases ◽  
Mechanism Of Action ◽  
Intracellular Signaling ◽  
Splice Variants ◽  
Nuclear Antigen ◽  
Proliferative Cell Nuclear Antigen ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein

Hypothalamic GHRH controls the release of GH from the pituitary gland and also acts as a growth factor in a variety of cancers. The mitogenetic activity of GHRH is exerted through the binding to the pituitary type receptor (pGHRH-R) and its splice variants, mainly SV1. The intracellular signaling pathways that are activated upon the binding of GHRH to the SV1 receptor have not been elucidated. HeLa cervical cancer cells do not express GHRH or GHRH receptors (GHRHRs) and thus do not respond to GHRH or GHRH antagonists. In order to elucidate the mechanism of action of SV1 receptor, we transfected HeLa cells with plasmids for pcDNA3-GHRHR or pcDNA3-SV1. The transfected cells responded to both GHRH (1–29)NH2 and GHRH antagonist MZ-5-156, as shown by an increase or decrease respectively in the proliferation rate in vitro and the expression of proliferative cell nuclear antigen. We also demonstrated that when the cells transfected with SV1 plasmid are stimulated with GHRH (1–29)NH2, SV1 receptor activates the mitogen-activated protein kinases pathway (MAPKs), as shown previously for the cells that express pGHRH-R. Our results show, for the first time, the activation of the MAPKs cascade by the SV1 receptor. Since SV1 receptor is found in various tumors and mediates the responses to GHRH and synthetic antagonists, our findings shed light on the mechanism of action of SV1 receptor in cancer cells.

scholarly journals A Network of Mitogen-Activated Protein Kinases Links G Protein-Coupled Receptors to the c-jun Promoter: a Role for c-Jun NH2-Terminal Kinase, p38s, and Extracellular Signal-Regulated Kinase 5

1999 ◽  
Vol 19 (6) ◽  
pp. 4289-4301 ◽  
Author(s):  
Maria Julia Marinissen ◽  
Mario Chiariello ◽  
Michael Pallante ◽  
J. Silvio Gutkind
Keyword(s):  
Signaling Pathway ◽  
Protein Kinases ◽  
G Protein ◽  
Intracellular Signaling ◽  
Temporal Integration ◽  
Regulatory Elements ◽  
G Protein Coupled Receptors ◽  
Mitogen Activated Protein Kinases ◽  
Mitogen Activated Protein ◽  
G Protein Coupled

ABSTRACT The expression of the c-jun proto-oncogene is rapidly induced in response to mitogens acting on a large variety of cell surface receptors. The resulting functional activity of c-Jun proteins appears to be critical for cell proliferation. Recently, we have shown that a large family of G protein-coupled receptors (GPCRs), represented by the m1 muscarinic receptor, can initiate intracellular signaling cascades that result in the activation of mitogen-activated protein kinases (MAPK) and c-Jun NH2-terminal kinases (JNK) and that the activation of JNK but not of MAPK correlated with a remarkable increase in the expression of c-jun mRNA. Subsequently, however, we obtained evidence that GPCRs can potently stimulate the activity of the c-jun promoter through MEF2 transcription factors, which do not act downstream from JNK. In view of these observations, we set out to investigate further the nature of the signaling pathway linking GPCRs to the c-jun promoter. Utilizing NIH 3T3 cells, we found that GPCRs can activate the c-jun promoter in a JNK-independent manner. Additionally, we demonstrated that these GPCRs can elevate the activity of novel members of the MAPK family, including ERK5, p38α, p38γ, and p38δ, and that the activation of certain kinases acting downstream from MEK5 (ERK5) and MKK6 (p38α and p38γ) is necessary to fully activate the c-jun promoter. Moreover, in addition to JNK, ERK5, p38α, and p38γ were found to stimulate the c-jun promoter by acting on distinct responsive elements. Taken together, these results suggest that the pathway linking GPCRs to the c-junpromoter involves the integration of numerous signals transduced by a highly complex network of MAPK, rather than resulting from the stimulation of a single linear protein kinase cascade. Furthermore, our findings suggest that each signaling pathway affects one or more regulatory elements on the c-jun promoter and that the transcriptional response most likely results from the temporal integration of each of these biochemical routes.

The Aqueous Extract of Radix Glycyrrhizae Stimulates Mitogen-Activated Protein Kinases and Nuclear Factor-κB in Jurkat T-Cells and THP-1 Monocytic Cells

2006 ◽  
Vol 34 (02) ◽  
pp. 263-278 ◽  
Author(s):  
Anthony S. L. Chan ◽  
Haihong Pang ◽  
Eric C. H. Yip ◽  
Yun K. Tam ◽  
Yung H. Wong
Keyword(s):  
Protein Kinases ◽  
Aqueous Extract ◽  
Intracellular Signaling ◽  
Nuclear Factor Κb ◽  
The Body ◽  
Jurkat Cells ◽  
Nuclear Factor ◽  
Mitogen Activated Protein Kinases ◽  
Radix Glycyrrhizae ◽  
Mitogen Activated Protein

Radix Glycyrrhizae (RG) is a medicinal herb extensively utilized in numerous Chinese medical formulae for coordinating the actions of various components in the recipes and strengthening the body functions. In this report, we demonstrate that the aqueous extract of Radix Glycyrrhizae is capable of stimulating the c-Jun N-terminal kinase and p38 subgroups of mitogen-activated protein kinases (MAPKs), and the nuclear factor-κB ( NF κ B ) in Jurkat T-lymphocytes. The activation magnitudes of MAPKs and NF κ B were dose-dependent ( EC 50 ≈ 1 mg/ml ) and time-dependent (maximal around 15–30 minutes). Stimulations of MAPKs and NF κ B were not associated with changes in intracellular Ca 2+ mobilization. Similar activation profiles of MAPK and NF κ B were obtained from THP-1 monocytes treated with the extract. In terms of chemotactic activity, the SDF-induced chemotaxis of Jurkat cells and THP-1 cells were inhibited by RG extract at 1–10 mg/ml, while a lower RG concentration (0.1–0.3 mg/ml) potentiated the SDF-induced chemotaxis for the former, but not the latter cell type. Given the fact that MAPKs and NF κ B are important signaling intermediates for lymphocyte activities, our results suggest that Radix Glycyrrhizae may contain active constituents capable of modulating immuno-responses through various intracellular signaling pathways.

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