Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: Potential proinflammatory mechanisms

2007 ◽  
Vol 56 (10) ◽  
pp. 3347-3357 ◽  
Author(s):  
Melissa J. Thiel ◽  
Caralee J. Schaefer ◽  
Mark E. Lesch ◽  
James L. Mobley ◽  
David T. Dudley ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Mouse Model ◽  
Map Kinase ◽  
Map Kinase Pathway ◽  
Kinase Pathway

scholarly journals Extracellular Zinc Triggers ERK-dependent Activation of Na+/H+Exchange in Colonocytes Mediated by the Zinc-sensing Receptor

2004 ◽  
Vol 279 (50) ◽  
pp. 51804-51816 ◽  
Author(s):  
Hagit Azriel-Tamir ◽  
Haleli Sharir ◽  
Betty Schwartz ◽  
Michal Hershfinkel
Keyword(s):  
Cell Proliferation ◽  
Map Kinase ◽  
Ph Homeostasis ◽  
Ht29 Cells ◽  
Intracellular Release ◽  
Map Kinase Pathway ◽  
Zinc Sensing ◽  
Multiple Signaling ◽  
Kinase Pathway

Extracellular zinc promotes cell proliferation and its deficiency leads to impairment of this process, which is particularly important in epithelial cells. We have recently characterized a zinc-sensing receptor (ZnR) linking extracellular zinc to intracellular release of calcium. In the present study, we addressed the role of extracellular zinc, acting via the ZnR, in regulating the MAP kinase pathway and Na+/H+exchange in colonocytes. We demonstrate that Ca2+release, mediated by the ZnR, induces phosphorylation of ERK1/2, which is highly metal-specific, mediated by physiological concentrations of extracellular Zn2+but not by Cd2+, Fe2+, Ni2+, or Mn2+. Desensitization of the ZnR by Zn2+, is followed by ∼90% inhibition of the Zn2+-dependent ERK1/2 phosphorylation, indicating that the ZnR is a principal link between extracellular Zn2+and ERK1/2 activation. Application of both the IP3pathway and PI 3-kinase antagonists largely inhibited Zn2+-dependent ERK1/2 phosphorylation. The physiological significance of the Zn2+-dependent activation of ERK1/2 was addressed by monitoring Na+/H+exchanger activity in HT29 cells and in native colon epithelium. Preincubation of the cells with zinc was followed by robust activation of Na+/H+exchange, which was eliminated by cariporide (0.5 μm); indicating that zinc enhances the activity of NHE1. Activation of NHE1 by zinc was totally blocked by the ERK1/2 inhibitor, U0126. Prolonged acidification, in contrast, stimulates NHE1 by a distinct pathway that is not affected by extracellular Zn2+or inhibitors of the MAP kinase pathway. Desensitization of ZnR activity eliminates the Zn2+-dependent, but not the prolonged acidification-dependent activation of NHE1, indicating that Zn2+-dependent activation of H+extrusion is specifically mediated by the ZnR. Our results support a role for extracellular zinc, acting through the ZnR, in regulating multiple signaling pathways that affect pH homeostasis in colonocytes. Furthermore activation of both, ERK and NHE1, by extracellular zinc may provide the mechanism linking zinc to enhanced cell proliferation.

scholarly journals Role of scaffolds in MAP kinase pathway specificity revealed by custom design of pathway-dedicated signaling proteins

2001 ◽  
Vol 11 (23) ◽  
pp. 1815-1824 ◽  
Author(s):  
Kendra Harris ◽  
Rachel E. Lamson ◽  
Bryce Nelson ◽  
Timothy R. Hughes ◽  
Matthew J. Marton ◽  
...  
Keyword(s):  
Map Kinase ◽  
Signaling Proteins ◽  
Custom Design ◽  
Map Kinase Pathway ◽  
Kinase Pathway

scholarly journals Counteracting resistance to targeted therapy in melanoma by inhibiting discoidin domain receptors

2019 ◽  
Author(s):  
Margaux Sala ◽  
Nathalie Allain ◽  
Elodie Henriet ◽  
Arnaud Uguen ◽  
Sylvaine Di-Tommaso ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Map Kinase ◽  
Braf V600e ◽  
First Line ◽  
Discoidin Domain Receptors ◽  
Map Kinase Pathway ◽  
Kinase Pathway ◽  
Resistant Cells

AbstractAnti-BRAF plus an anti-MEK is currently used in first line for the management of patients presenting metastatic melanomas harboring the BRAF V600E mutation. However, the main issue during targeted therapy is the acquisition of cellular resistance in 80% of the patients, which is associated with an increased metastasis due to the hyperactivation of MAP kinase pathway. Previous reports have indicated that Discoidin Domain Receptors (DDRs) 1 and 2 can activate this pathway. To study the role of DDRs in melanoma cell resistance to targeted therapy, we first determined that DDRs are overexpressed in vemurafenib resistant cells compared to sensitive cells. We demonstrated that DDRs depletion or inactivation by DDRs inhibitors such as dasatinib or CR-13542 reduces tumor cell proliferation, due to a decrease of MAP kinase pathway activity in resistant cells. Finally, we confirmed these results in vivo in a xenograft mouse model and show that DDRs could be new therapeutic targets in resistant patients with metastatic melanoma. We propose that dasatinib could be a second-line treatment after the bi-therapy in resistant patients overexpressing DDRs.

scholarly journals The role of EGFR/ERK/ELK-1 MAP kinase pathway in the underlying damage to diabetic rat skin

2013 ◽  
Vol 58 (2) ◽  
pp. 101 ◽  
Author(s):  
Jianzhong Zhang ◽  
Xinhong Ge ◽  
Yaning Jiao ◽  
Zhiyun Shi ◽  
Nan Yu ◽  
...  
Keyword(s):  
Map Kinase ◽  
Diabetic Rat ◽  
Rat Skin ◽  
Map Kinase Pathway ◽  
Kinase Pathway

scholarly journals Role of Tec1 in the Development, Architecture, and Integrity of Sexual Biofilms of Candida albicans

2015 ◽  
Vol 14 (3) ◽  
pp. 228-240 ◽  
Author(s):  
Karla J. Daniels ◽  
Thyagarajan Srikantha ◽  
Claude Pujol ◽  
Yang-Nim Park ◽  
David R. Soll
Keyword(s):  
Map Kinase ◽  
White Blood Cells ◽  
Silicone Elastomer ◽  
Minor Role ◽  
Matrix Deposition ◽  
Initial Adhesion ◽  
Map Kinase Pathway ◽  
Biofilm Development ◽  
Kinase Pathway

ABSTRACTMTL-homozygous (a/aor α/α) white cells form a complex sexual biofilm that exhibits the same architecture as that ofMTL-heterozygous (a/α) pathogenic biofilms. However, the former is regulated by the mitogen-activated protein (MAP) kinase pathway, while the latter is regulated by the Ras1/cyclic AMP (cAMP) pathway. We previously demonstrated that in the formation of anMTL-homozygous, mature (48 h) sexual biofilm in RPMI 1640 medium, the MAP kinase pathway targets Tec1 rather than Cph1, the latter of which is the target of the same pathway, but for the opaque cell mating response. Here we continued our analysis of the role of Tec1 by comparing the effects of deletingTEC1on initial adhesion to silicone elastomer, high-resolution confocal microscopy assessments of the stages and cellular phenotypes during the 48 h of biofilm development, human white cell penetration, and biofilm fragility. We show that although Tec1 plays only a minor role in initial adhesion to the silicone elastomer, it does play a major role in the growth of the basal yeast cell polylayer, vertical extension of hyphae and matrix deposition in the upper portion of the biofilm, final biofilm thickness, penetrability of human white blood cells, and final biofilm integrity (i.e., resistance to fluid flow). These results provide a more detailed description of normal biofilm development and architecture and confirm the central role played by the transcription factor Tec1 in the biofilm model employed here.

Tie2Cre B-Raf flox/flox Mice Reveal a Role for B-Raf in Tpo-Mediated Thrombopoiesis and Survival of Mature Megakaryocytes in Adult Hematopoiesis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 200-200
Author(s):  
Tamihiro Kamata ◽  
Jing Kang ◽  
Alcino Silva ◽  
Rong Wang ◽  
Andrew D. Leavitt
Keyword(s):  
Bone Marrow ◽  
Map Kinase ◽  
Chimeric Mouse ◽  
Kinase Signaling ◽  
Western Blots ◽  
Map Kinase Signaling ◽  
Map Kinase Pathway ◽  
Kinase Pathway

Abstract Thrombopoietin (Tpo) is the primary cytokine regulator of megakaryocytopoiesis. Tpo engagement of its receptor, Mpl, activates the classic MAP kinase (Raf/MEK/ERK) pathway, but the biological role of MAP kinase signaling in megakaryocytopoiesis remains poorly defined. Raf family kinases control signal flow through the classic MAP kinase pathway from activated cytokine receptors. We therefore undertook a genetic approach to understand the role of MAP kinase signaling and to identify which Raf family member is important for megakaryocytopoiesis. Using data from in vitro B-raf-/- ES cell cultures, fetal liver hematopoietic cells from mid-gestation B-raf-/- embryos, and B-raf-/- chimeric mice, we recently reported that B-Raf acts in a cell autonomous manner to quantitatively affect megakaryocytopoiesis. However, limitations of the chimeric mouse model, and mid-gestation lethality of B-raf-/- embryos precluded a detailed mechanistic understanding of B-Raf activity or the evaluation of B-Raf in adult megakaryocytopoiesis. We therefore generated tissue-restricted B-Raf deficient mice by crossing B-rafflox/flox mice with mice expressing Cre recombinase controlled by the Tie2 promoter/enhancer. The Tie2Cre+/B-rafflox/flox mice were born with normal Mendelian genetics and without gross abnormalities. Circulating leukocytes demonstrated complete recombination of the floxed B-Raf allele, and western blots showed undetectable B-Raf expression in platelet, spleen, and thymus lysates, consistent with complete hematopoietic Cre-mediated recombination. Steady state platelet counts were not altered in the B-Raf deficient animals at baseline: Tie2Cre+/B-rafflox/flox mice = 788 +/−57 x 103/mm3; Tie2Cre-/B-rafflox/flox mice 800 +/−40 x 103/mm3 (p=0.76, n=4). However, Tie2Cre+/B-rafflox/flox mice had a markedly impaired platelet count rise following Tpo injection, with peak counts of 3,375 +/−752 x 103/mm3 compared with 5,320 +/−606 x 103/mm3 for Tie2Cre-/B-rafflox/flox mice (p=0.0147, n=4) at 6 days post injection. In vitro expansion of CD41+ cells from Tie2Cre+/B-rafflox/flox bone marrow was only a third that of control mice, suggesting that the impaired in vivo platelet rise following Tpo reflects, at least in part, a decreased expansion of megakaryocyte lineage cells. Day 4 Tie2Cre+/B-rafflox/flox bone marrow cultures also yielded decreased low (2N-8N) and high (>32N) ploidy CD41+ cells compared with marrow from Tie2Cre-/B-rafflox/flox mice, while intermediate (16N-32N) ploidy CD41+ megakaryocytes were relatively preserved. TUNEL analysis revealed increased apoptotic death of the high ploidy (>32N) cells, a second possible mechanism contributing to the impaired platelet rise following Tpo injection. Together, our data demonstrate that the B-Raf/MAP kinase pathway is required for normal adult Tpo-induced thrombopoiesis through its effect on megakaryocyte lineage expansion and apoptotic cell death of mature megakaryocytes. Additional analysis is now underway to more fully define the role of B-Raf in megakaryocytopoiesis, including detailed biochemical studies to determine how the absence of B-Raf impacts intracellular signaling during this complex developmental process.

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