scholarly journals ERK1,2 Signalling Pathway along the Nephron and Its Role in Acid-base and Electrolytes Balance

2019 ◽  
Vol 20 (17) ◽  
pp. 4153 ◽  
Author(s):  
Giovanna Capolongo ◽  
Yoko Suzumoto ◽  
Mariavittoria D’Acierno ◽  
Mariadelina Simeoni ◽  
Giovambattista Capasso ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Mapk Signaling ◽  
Signalling Pathway ◽  
Renal Diseases ◽  
Cellular Functions ◽  
Acid Base ◽  
Mapk Activity ◽  
Extracellular Signal ◽  
Wide Range ◽  
Mitogen Activated Protein

Mitogen-activated protein kinases (MAPKs) are intracellular molecules regulating a wide range of cellular functions, including proliferation, differentiation, apoptosis, cytoskeleton remodeling and cytokine production. MAPK activity has been shown in normal kidney, and its over-activation has been demonstrated in several renal diseases. The extracellular signal-regulated protein kinases (ERK 1,2) signalling pathway is the first described MAPK signaling. Intensive investigations have demonstrated that it participates in the regulation of ureteric bud branching, a fundamental process in establishing final nephron number; in addition, it is also involved in the differentiation of the nephrogenic mesenchyme, indicating a key role in mammalian kidney embryonic development. In the present manuscript, we show that ERK1,2 signalling mediates several cellular functions also in mature kidney, describing its role along the nephron and demonstrating whether it contributes to the regulation of ion channels and transporters implicated in acid-base and electrolytes homeostasis.

scholarly journals Targeting the MDSCs of Tumors In Situ With Inhibitors of the MAPK Signaling Pathway to Promote Tumor Regression

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiayun Yu ◽  
Hanwen Li ◽  
Zongliang Zhang ◽  
Weimin Lin ◽  
Xiawei Wei ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Protein Kinases ◽  
Tumor Regression ◽  
Suppressor Cells ◽  
Mapk Signaling ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

Myeloid-derived suppressor cells (MDSCs) are one of the major components of the tumor microenvironment. Evidence has shown differences in the functions and fates of MDSCs in the tumor tissue and the periphery. However, the exact mechanism that regulates MDSC function has not been completely clarified. In this study, we performed RNA sequencing of MDSCs derived from the spleen and tumor. Based on the results of our RNA-seq analysis, mitogen-activated protein kinases (MAPK) were significantly increased in tumor polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs). Subsequently, 3 major MAPK pathways, including extracellular signal-regulated protein kinases (ERK), p38 and c-Jun NH2-terminal kinases (JNK), were studied to analyze the role of MAPKs in MDSCs. The ERK 1/2 inhibitor SCH772984 and the JNK inhibitor SP600125 significantly increased the apoptosis of both PMN-MDSCs and M-MDSCs in vitro. In addition, SCH772984 exerted a strong effect on inhibiting tumor growth. The flow cytometry analysis showed significant increases in the ratio of M1:M2 tumor-associated macrophages, meanwhile the number of CD4+, CD8+, CD4+CD69+ and CD8+CD69+ lymphocytes were increased after SCH772984 treatment. Our findings established the effect of MAPKs on the tumor microenvironment via MDSCs and may facilitate the development of new antitumor strategies.

scholarly journals Mitogen-Activated Protein Kinases and Hypoxic/Ischemic Nephropathy

2016 ◽  
Vol 39 (3) ◽  
pp. 1051-1067 ◽  
Author(s):  
Fengbao Luo ◽  
Jian Shi ◽  
Qianqian Shi ◽  
Xianlin Xu ◽  
Ying Xia ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Protein Kinases ◽  
Kidney Injury ◽  
Pathological Feature ◽  
Mitogen Activated Protein Kinases ◽  
Ischemic Nephropathy ◽  
Extracellular Signal ◽  
Wide Range ◽  
Hypoxia Ischemia ◽  
Mitogen Activated Protein

Tissue hypoxia/ischemia is a pathological feature of many human disorders including stroke, myocardial infarction, hypoxic/ischemic nephropathy, as well as cancer. In the kidney, the combination of limited oxygen supply to the tissues and high oxygen demand is considered the main reason for the susceptibility of the kidney to hypoxic/ischemic injury. In recent years, increasing evidence has indicated that a reduction in renal oxygen tension/blood supply plays an important role in acute kidney injury, chronic kidney disease, and renal tumorigenesis. However, the underlying signaling mechanisms, whereby hypoxia alters cellular behaviors, remain poorly understood. Mitogen-activated protein kinases (MAPKs) are key signal-transducing enzymes activated by a wide range of extracellular stimuli, including hypoxia/ischemia. There are four major family members of MAPKs: the extracellular signal-regulated kinases-1 and -2 (ERK1/2), the c-Jun N-terminal kinases (JNK), p38 MAPKs, and extracellular signal-regulated kinase-5 (ERK5/BMK1). Recent studies, including ours, suggest that these MAPKs are differentially involved in renal responses to hypoxic/ischemic stress. This review will discuss their changes in hypoxic/ischemic pathophysiology with acute kidney injury, chronic kidney diseases and renal carcinoma.

scholarly journals Ras Mutation Impairs Epithelial Barrier Function to a Wide Range of Nonelectrolytes

2005 ◽  
Vol 16 (12) ◽  
pp. 5538-5550 ◽  
Author(s):  
James M. Mullin ◽  
James M. Leatherman ◽  
Mary Carmen Valenzano ◽  
Erika Rendon Huerta ◽  
Jon Verrechio ◽  
...  
Keyword(s):  
Tight Junctions ◽  
Mitogen Activated Protein Kinase ◽  
Epithelial Barrier ◽  
Epithelial Barrier Function ◽  
Downstream Effects ◽  
Extracellular Signal ◽  
Wide Range ◽  
Mitogen Activated Protein ◽  
Protein Kinase Signaling ◽  
Kinase Signaling Pathway

Although ras mutations have been shown to affect epithelial architecture and polarity, their role in altering tight junctions remains unclear. Transfection of a valine-12 mutated ras construct into LLC-PK1 renal epithelia produces leakiness of tight junctions to certain types of solutes. Transepithelial permeability of d-mannitol increases sixfold but transepithelial electrical resistance increases >40%. This indicates decreased paracellular permeability to NaCl but increased permeability to nonelectrolytes. Permeability increases to d-mannitol (Mr 182), polyethylene glycol (Mr 4000), and 10,000-Mr methylated dextran but not to 2,000,000-Mr methylated dextran. This implies a “ceiling” on the size of solutes that can cross a ras-mutated epithelial barrier and therefore that the increased permeability is not due to loss of cells or junctions. Although the abundance of claudin-2 declined to undetectable levels in the ras-overexpressing cells compared with vector controls, levels of occludin and claudins 1, 4, and 7 increased. The abundance of claudins-3 and -5 remained unchanged. An increase in extracellular signal-regulated kinase-2 phosphorylation suggests that the downstream effects on the tight junction may be due to changes in the mitogen-activated protein kinase signaling pathway. These selective changes in permeability may influence tumorigenesis by the types of solutes now able to cross the epithelial barrier.

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 Activation of Extracellular Signal-Related Protein Kinases 1 and 2 of the Mitogen-Activated Protein Kinase Family by Lipopolysaccharide Requires Plasma in Neutrophils from Adults and Newborns

2001 ◽  
Vol 69 (5) ◽  
pp. 3143-3149 ◽  
Author(s):  
S. Bonner ◽  
S. R. Yan ◽  
D. M. Byers ◽  
R. Bortolussi
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Oxidative Burst ◽  
Mitogen Activated Protein Kinase ◽  
Related Protein ◽  
Extracellular Signal ◽  
Oxidative Response ◽  
Mitogen Activated Protein ◽  
Mediated Priming

ABSTRACT Neutrophils exposed to low concentrations of gram-negative lipopolysaccharide (LPS) become primed and have an increased oxidative response to a second stimulus (e.g., formyl-methionyl-leucyl-phenylalanine [fMLP]). In studies aimed at understanding newborn sepsis, we have shown that neutrophils of newborns are not primed in response to LPS. To further understand the processes involved in LPS-mediated priming of neutrophils, we explored the role of extracellular signal-related protein kinases (ERK 1 and 2) of the mitogen-activated protein kinase family. We found that LPS activated ERK 1 and 2 in cells of both adults and newborns and that activation was plasma dependent (maximal at ≥5%) through LPS-binding protein. Although fibronectin in plasma is required for LPS-mediated priming of neutrophils of adults assessed by fMLP-triggered oxidative burst, it was not required for LPS-mediated activation of ERK 1 and 2. LPS-mediated activation was dose and time dependent; maximal activation occurred with approximately 5 ng of LPS per ml and at 10 to 40 min. We used the inhibitor PD 98059 to study the role of ERK 1 and 2 in the LPS-primed fMLP-triggered oxidative burst. While Western blotting showed that 100 μM PD 98059 completely inhibited LPS-mediated ERK activation, oxidative response to fMLP by a chemiluminescence assay revealed that the same concentration inhibited the LPS-primed oxidative burst by only 40%. We conclude that in neutrophils, LPS-mediated activation of ERK 1 and 2 requires plasma and that this activation is not dependent on fibronectin. In addition, we found that the ERK pathway is not responsible for the lack of LPS priming in neutrophils of newborns but may be required for 40% of the LPS-primed fMLP-triggered oxidative burst in cells of adults.

scholarly journals Roles of Mitogen-Activated Protein Kinases in Osteoclast Biology

2018 ◽  
Vol 19 (10) ◽  
pp. 3004 ◽  
Author(s):  
Kyunghee Lee ◽  
Incheol Seo ◽  
Mun Choi ◽  
Daewon Jeong
Keyword(s):  
Bone Resorption ◽  
Protein Kinases ◽  
Current Knowledge ◽  
Osteoclast Differentiation ◽  
Cathepsin K ◽  
Proton Pumping ◽  
Mitogen Activated Protein Kinases ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Inorganic Mineral

Bone undergoes continuous remodeling, which is homeostatically regulated by concerted communication between bone-forming osteoblasts and bone-degrading osteoclasts. Multinucleated giant osteoclasts are the only specialized cells that degrade or resorb the organic and inorganic bone components. They secrete proteases (e.g., cathepsin K) that degrade the organic collagenous matrix and establish localized acidosis at the bone-resorbing site through proton-pumping to facilitate the dissolution of inorganic mineral. Osteoporosis, the most common bone disease, is caused by excessive bone resorption, highlighting the crucial role of osteoclasts in intact bone remodeling. Signaling mediated by mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38, has been recognized to be critical for normal osteoclast differentiation and activation. Various exogenous (e.g., toll-like receptor agonists) and endogenous (e.g., growth factors and inflammatory cytokines) stimuli contribute to determining whether MAPKs positively or negatively regulate osteoclast adhesion, migration, fusion and survival, and osteoclastic bone resorption. In this review, we delineate the unique roles of MAPKs in osteoclast metabolism and provide an overview of the upstream regulators that activate or inhibit MAPKs and their downstream targets. Furthermore, we discuss the current knowledge about the differential kinetics of ERK, JNK, and p38, and the crosstalk between MAPKs in osteoclast metabolism.

scholarly journals mTORC2 Is Involved in the Induction of RSK Phosphorylation by Serum or Nutrient Starvation

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1567
Author(s):  
Po-Chien Chou ◽  
Swati Rajput ◽  
Xiaoyun Zhao ◽  
Chadni Patel ◽  
Danielle Albaciete ◽  
...  
Keyword(s):  
Protein Kinases ◽  
Mitogen Activated Protein Kinase ◽  
S6 Kinase ◽  
Agc Kinases ◽  
Extracellular Signal Regulated Kinase ◽  
Mechanistic Target Of Rapamycin ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Inhibition Of Glycolysis ◽  
Ribosomal S6 Kinase

Cells adjust to nutrient fluctuations to restore metabolic homeostasis. The mechanistic target of rapamycin (mTOR) complex 2 responds to nutrient levels and growth signals to phosphorylate protein kinases belonging to the AGC (Protein Kinases A,G,C) family such as Akt and PKC. Phosphorylation of these AGC kinases at their conserved hydrophobic motif (HM) site by mTORC2 enhances their activation and mediates the functions of mTORC2 in cell growth and metabolism. Another AGC kinase family member that is known to undergo increased phosphorylation at the homologous HM site (Ser380) is the p90 ribosomal S6 kinase (RSK). Phosphorylation at Ser380 is facilitated by the activation of the mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) in response to growth factor stimulation. Here, we demonstrate that optimal phosphorylation of RSK at this site requires an intact mTORC2. We also found that RSK is robustly phosphorylated at Ser380 upon nutrient withdrawal or inhibition of glycolysis, conditions that increase mTORC2 activation. However, pharmacological inhibition of mTOR did not abolish RSK phosphorylation at Ser380, indicating that mTOR catalytic activity is not required for this phosphorylation. Since RSK and SIN1β colocalize at the membrane during serum restimulation and acute glutamine withdrawal, mTORC2 could act as a scaffold to enhance RSK HM site phosphorylation. Among the known RSK substrates, the CCTβ subunit of the chaperonin containing TCP-1 (CCT) complex had defective phosphorylation in the absence of mTORC2. Our findings indicate that the mTORC2-mediated phosphorylation of the RSK HM site could confer RSK substrate specificity and reveal that RSK responds to nutrient fluctuations.

scholarly journals Anti-Melanogenic Effects of Bergamottin via Mitogen-Activated Protein Kinases and Protein Kinase B Signaling Pathways

2019 ◽  
Vol 14 (7) ◽  
pp. 1934578X1986210
Author(s):  
You Chul Chung ◽  
Yun Beom Kim ◽  
Bong Seok Kim ◽  
Chang-Gu Hyun
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Protein Kinase B ◽  
Positive Control ◽  
Akt Inhibitor ◽  
Mitogen Activated Protein Kinases ◽  
Melanocyte Stimulating Hormone ◽  
B16f10 Cells ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

In this study, we examined the inhibitory effects of bergamottin on melanogenesis in B16F10 murine melanoma cells, together with its effects on the mechanism of melanin synthesis. α-Melanocyte stimulating hormone-stimulated B16F10 cells were treated with various concentrations of bergamottin, with arbutin as a positive control. Bergamottin significantly decreased the melanin content and tyrosinase activity without showing any cytotoxicity. In addition, bergamottin treatment significantly downregulated the expression of tyrosinase-related protein-1,2 and tyrosinase by suppressing the expression of microphthalmia-associated transcription factor. The phosphorylation status of mitogen-activated protein kinases (MAPKs) and protein kinase B (AKT) was examined to determine the mechanism underlying the antimelanogenic effects of bergamottin. Bergamottin treatment increased the phosphorylation of extracellular signal-regulated kinase (ERK) and AKT, but decreased the phosphorylation of p38 and c-Jun N-terminal kinase in the B16F10 cells. Moreover, the use of PD98059 (ERK inhibitor) and LY294002 (AKT inhibitor) corroborated these findings, indicating that bergamottin inhibits melanogenesis via the MAPKase and AKT signaling pathway. Thus, bergamottin has potential for treating hyperpigmentation disorders and can be a promising chemical for skin-whitening in the cosmetic industry.

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