scholarly journals Osmotic swelling-induced activation of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2 in Intestine 407 cells involves the Ras/Raf-signalling pathway

1998 ◽  
Vol 331 (3) ◽  
pp. 863-869 ◽  
Author(s):  
Thea van Der WIJK ◽  
Jannette DORRESTIJN ◽  
Shuh NARUMIYA ◽  
J. Antonie MAASSEN ◽  
Hugo R. De JONGE ◽  
...  
Keyword(s):  
Cell Volume ◽  
Protein Kinases ◽  
Kinase Inhibitor ◽  
Cell Volume Regulation ◽  
Dominant Negative ◽  
Signalling Pathway ◽  
Volume Control ◽  
Direct Role ◽  
Extracellular Signal ◽  
Stimulation Of

Human Intestine 407 cells respond to hypo-osmotic stress with a rapid stimulation of compensatory ionic conductances accompanied by a transient increase in the activity of the extracellular-signal-regulated protein kinases Erk-1 and Erk-2. In this study, we examined the upstream regulators of hypotonicity-induced Erk-1/Erk-2 activation and their possible role in cell-volume regulation. The hypotonicity-provoked Erk-1/Erk-2 activation was greatly reduced in cells pretreated with the specific mitogen-activated/Erk-activating kinase inhibitor PD098059 and was preceded by a transient stimulation of Raf-1. Pretreatment of the cells with PMA, GF 109203X, wortmannin or Clostridium botulinum C3 exoenzyme did not appreciably affect the hypotonicity-provoked Erk-1/Erk-2 stimulation, suggesting the osmosensitive signalling pathway to be largely independent of protein kinase C and p21rho. In contrast, expression of dominant negative RasN17 completely abolished the hypotonicity-induced Erk-1/Erk-2 activation. Stimulation of the swelling-induced ion efflux was independent of activation of these mitogen-activated protein kinases, as revealed by hypotonicity-provoked isotope efflux from 125I-- and 86Rb+-loaded cells after pretreatment with PD098059 and after expression of RasN17. In addition, the epidermal-growth-factor-induced potentiation of the hypotonicity-provoked anionic response did not depend on the increase in Erk-1/Erk-2 activity but, instead, was found to depend on Ca2+ influx. Taken together, these results indicate that hypotonic stress induces Erk-1/Erk-2 activation through the Ras/Raf-signalling pathway, and argue against a direct role for this pathway in cell-volume control.

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 Contrasting effects of ERK on tight junction integrity in differentiated and under-differentiated Caco-2 cell monolayers

2010 ◽  
Vol 433 (1) ◽  
pp. 51-63 ◽  
Author(s):  
Sudhir Aggarwal ◽  
Takuya Suzuki ◽  
William L. Taylor ◽  
Aditi Bhargava ◽  
Radhakrishna K. Rao
Keyword(s):  
Protein Kinase ◽  
Tight Junction ◽  
Tight Junctions ◽  
Kinase Inhibitor ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Cell Monolayers ◽  
Differentiated Cells ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ERK (extracellular-signal-regulated kinase) activation leads to disruption of tight junctions in some epithelial monolayers, whereas it prevents disruption of tight junctions in other epithelia. The factors responsible for such contrasting influences of ERK on tight junction integrity are unknown. The present study investigated the effect of the state of cell differentiation on ERK-mediated regulation of tight junctions in Caco-2 cell monolayers. EGF (epidermal growth factor) potentiated H2O2-induced tight junction disruption in under-differentiated cell monolayers, which was attenuated by the MEK [MAPK (mitogen-activated protein kinase)/ERK kinase] inhibitor U0126. In contrast, EGF prevented H2O2-induced disruption of tight junctions in differentiated cell monolayers, which was also attenuated by U0126. Knockdown of ERK1/2 enhanced tight junction integrity and accelerated assembly of tight junctions in under-differentiated cell monolayers, whereas it had the opposite effect in differentiated cell monolayers. Regulated expression of wild-type and constitutively active MEK1 disrupted tight junctions, and the expression of dominant-negative MEK1 enhanced tight junction integrity in under-differentiated cells, whereas contrasting responses were recorded in differentiated cells. EGF prevented both H2O2-induced association of PP2A (protein phosphatase 2A), and loss of association of PKCζ (protein kinase Cζ), with occludin by an ERK-dependent mechanism in differentiated cell monolayers, but not in under-differentiated cell monolayers. Active ERK was distributed in the intracellular compartment in under-differentiated cell monolayers, whereas it was localized mainly in the perijunctional region in differentiated cell monolayers. Thus ERK may exhibit its contrasting influences on tight junction integrity in under-differentiated and differentiated epithelial cells by virtue of differences in its subcellular distribution and ability to regulate the association of PKCζ and PP2A with tight junction proteins.

scholarly journals Trypanosoma cruzi Infection Activates Extracellular Signal-Regulated Kinase in Cultured Endothelial and Smooth Muscle Cells

2004 ◽  
Vol 72 (9) ◽  
pp. 5274-5282 ◽  
Author(s):  
Shankar Mukherjee ◽  
Huan Huang ◽  
Stefka B. Petkova ◽  
Chris Albanese ◽  
Richard G. Pestell ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Trypanosoma Cruzi ◽  
Smooth Muscle Cells ◽  
Kinase Inhibitor ◽  
Umbilical Vein ◽  
Muscle Cells ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Activator Protein 1 ◽  
Extracellular Signal

ABSTRACT Trypanosoma cruzi infection causes cardiomyopathy and vasculopathy. We examined the consequence of this infection for the mitogen-activated protein kinase (MAPK) pathways, which regulate cell proliferation in cultured human umbilical vein endothelial and vascular smooth muscle cells. Infection of these cells resulted in activation of extracellular signal-regulated kinases 1and 2 (ERK1/2) but not c-Jun N-terminal kinase or p38 MAPK. Treatment of these cells with the MAPK kinase inhibitor PD98059 prior to infection blocked the increase in phosphorylated ERK1/2 seen with infection. Heat-killed parasites did not activate ERK1/2, indicating that activation of ERK1/2 was dependent on infection of these cells by live parasites. Furthermore, transfection with dominant-negative Raf(301) or Ras(N17) constructs reduced the infection-associated levels of phospho-ERK1/2, indicating that the activation of ERK1/2 involved the Ras-Raf-ERK pathway. Infection also resulted in an increase in activator protein 1 (AP-1) activity, which was inhibited by transfection with a dominant-negative Raf(301) construct. T. cruzi-infected endothelial cells secreted endothelin-1 and interleukin-1β, which activated ERK1/2 and induced cyclin D1 expression in uninfected smooth muscle cells. These data suggest a possible molecular paradigm for the pathogenesis of the vasculopathy and the cardiovascular remodeling associated with T. cruzi infection.

scholarly journals ERK1/2 Activity Is Critical for the Outcome of Ischemic Stroke

2022 ◽  
Vol 23 (2) ◽  
pp. 706
Author(s):  
Constanze Schanbacher ◽  
Michael Bieber ◽  
Yvonne Reinders ◽  
Deya Cherpokova ◽  
Christina Teichert ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Kinase Inhibitor ◽  
Infarct Volume ◽  
Neurological Deficits ◽  
Wild Type ◽  
Tight Control ◽  
Raf Kinase ◽  
Raf Kinase Inhibitor Protein ◽  
Extracellular Signal ◽  
Stimulation Of

Ischemic disorders are the leading cause of death worldwide. The extracellular signal-regulated kinases 1 and 2 (ERK1/2) are thought to affect the outcome of ischemic stroke. However, it is under debate whether activation or inhibition of ERK1/2 is beneficial. In this study, we report that the ubiquitous overexpression of wild-type ERK2 in mice (ERK2wt) is detrimental after transient occlusion of the middle cerebral artery (tMCAO), as it led to a massive increase in infarct volume and neurological deficits by increasing blood–brain barrier (BBB) leakiness, inflammation, and the number of apoptotic neurons. To compare ERK1/2 activation and inhibition side-by-side, we also used mice with ubiquitous overexpression of the Raf-kinase inhibitor protein (RKIPwt) and its phosphorylation-deficient mutant RKIPS153A, known inhibitors of the ERK1/2 signaling cascade. RKIPwt and RKIPS153A attenuated ischemia-induced damages, in particular via anti-inflammatory signaling. Taken together, our data suggest that stimulation of the Raf/MEK/ERK1/2-cascade is severely detrimental and its inhibition is rather protective. Thus, a tight control of the ERK1/2 signaling is essential for the outcome in response to ischemic stroke.

scholarly journals Ouabain-Induced Cytoplasmic Vesicles and Their Role in Cell Volume Maintenance

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
M. A. Russo ◽  
E. Morgante ◽  
A. Russo ◽  
G. D. van Rossum ◽  
M. Tafani
Keyword(s):  
Cell Volume ◽  
Cell Volume Regulation ◽  
Extracellular Fluid ◽  
Bile Canaliculus ◽  
Volume Control ◽  
Osmotic Gradient ◽  
Water Composition ◽  
Mammalian Tissues ◽  
Metabolic Conditions ◽  
Cell Volume Control

Cellular swelling is controlled by an active mechanism of cell volume regulation driven by a Na+/K+-dependent ATPase and by aquaporins which translocate water along the osmotic gradient. Na+/K+-pump may be blocked by ouabain, a digitalic derivative, by inhibition of ATP, or by drastic ion alterations of extracellular fluid. However, it has been observed that some tissues are still able to control their volume despite the presence of ouabain, suggesting the existence of other mechanisms of cell volume control. In 1977, by correlating electron microscopy observation with ion and water composition of liver slices incubated in different metabolic conditions in the presence or absence of ouabain, we observed that hepatocytes were able to control their volume extruding water and recovering ion composition in the presence of ouabain. In particular, hepatocytes were able to sequester ions and water in intracellular vesicles and then secrete them at the bile canaliculus pole. We named this “vesicular mechanism of cell volume control.” Afterward, this mechanism has been confirmed by us and other laboratories in several mammalian tissues. This review summarizes evidences regarding this mechanism, problems that are still pending, and questions that need to be answered. Finally, we shortly review the importance of cell volume control in some human pathological conditions.

scholarly journals Reactive oxygen species production via NADPH oxidase mediates TGF-β-induced cytoskeletal alterations in endothelial cells

2005 ◽  
Vol 289 (4) ◽  
pp. F816-F825 ◽  
Author(s):  
Taishan Hu ◽  
Satish P. RamachandraRao ◽  
Senthuran Siva ◽  
Cathryn Valancius ◽  
Yanqing Zhu ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Endothelial Cells ◽  
Nadph Oxidase ◽  
Kinase Inhibitor ◽  
Reactive Oxygen ◽  
Dominant Negative ◽  
Type I ◽  
Ros Production ◽  
Oxygen Species ◽  
Stimulation Of

Cytoskeletal alterations in endothelial cells have been linked to nitric oxide generation and cell-cell interactions. Transforming growth factor (TGF)-β has been described to affect cytoskeletal rearrangement in numerous cell types; however, the underlying pathway is unclear. In the present study, we found that human umbilical vein endothelial cells (HUVEC) have marked cytoskeletal alterations with short-term TGF-β treatment resulting in filipodia formation and F-actin assembly. The cytoskeletal alterations were blocked by the novel TGF-β type I receptor/ALK5 kinase inhibitor (SB-505124) but not by the p38 kinase inhibitor (SB-203580). TGF-β also induced marked stimulation of reactive oxygen species (ROS) within 5 min of TGF-β exposure. TGF-β stimulation of ROS was mediated by the NAPDH oxidase homolog Nox4 as DPI, an inhibitor of NADPH oxidase, and dominant-negative Nox4 adenovirus blocked ROS production. Finally, inhibition of ROS with ROS scavengers or dominant-negative Nox4 blocked the TGF-β effect on cytoskeleton changes in endothelial cells. In conclusion, our studies show for the first time that TGF-β-induced ROS production in human endothelial cells is via Nox4 and that TGF-β alteration of cytoskeleton in HUVEC is mediated via a Nox4-dependent pathway.

Involvement of tyrosine kinase and PI3K in the regulation of OAT3-mediated estrone sulfate transport in isolated rabbit renal proximal tubules

2005 ◽  
Vol 289 (5) ◽  
pp. F1057-F1064 ◽  
Author(s):  
S. Soodvilai ◽  
S. H. Wright ◽  
W. H. Dantzler ◽  
V. Chatsudthipong
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Organic Anion ◽  
Proximal Tubules ◽  
Dependent Manner ◽  
Renal Proximal Tubules ◽  
Estrone Sulfate ◽  
Extracellular Signal ◽  
Stimulation Of

It was shown previously that OAT3 activity was differentially regulated by protein kinases including MAPK, PKA, and PKC. The present study investigated the short-term effect of tyrosine kinase and phosphatidylinositol 3-kinase (PI3K) on OAT3-mediated organic anion transport in S2 segments of renal proximal tubules. Genistein, a tyrosine kinase inhibitor, and wortmannin, a PI3K inhibitor, inhibited transport of estrone sulfate, a prototypic substrate for OAT3, in a dose-dependent manner. Previously, we showed that epidermal growth factor (EGF) stimulated OAT3 activity via the MAPK pathway. In the present study, we investigated whether EGF-stimulated OAT3 activity was dependent on tyrosine kinase and PI3K. We showed that EGF stimulation of OAT3 was reduced by inhibition of tyrosine kinase or PI3K, suggesting that they play a role in the stimulatory process. Inhibitory effects also indicated that tyrosine kinase and PI3K are involved in the MAPK pathway for EGF stimulation of OAT3 in intact renal proximal tubules, with PI3K acting upstream and tyrosine kinase acting downstream of mitogen-activated/extracellular signal-regulated kinase kinase activation.

Protein Kinases, Phosphatases, and the Control of Cell Volume

Physiology ◽  
1992 ◽  
Vol 7 (5) ◽  
pp. 232-237 ◽  
Author(s):  
S Grinstein ◽  
W Furuya ◽  
L Bianchini
Keyword(s):  
Protein Kinase ◽  
Solute Transport ◽  
Cell Volume ◽  
Protein Kinases ◽  
Volume Change ◽  
Transport Systems ◽  
Volume Control ◽  
Animal Cells

Animal cells regulate their size in isotonic and anisotonic conditions by activating volume-sensitive solute transport systems. Recent evidence suggests that protein phosporylation/dephosphorylation is involved in volume control. These observations are integrated into a model consisting of a single volume-sensing device, a transducing element which may be a protein kinase, and two types of volume change effectors.

scholarly journals Role of phosphoinositide 3-kinase and the Cbl adaptor protein in coupling the α4β1 integrin to mitogen-activated protein kinase signalling

2000 ◽  
Vol 345 (2) ◽  
pp. 385-392 ◽  
Author(s):  
Lisa D. FINKELSTEIN ◽  
Yoji SHIMIZU
Keyword(s):  
Protein Kinase ◽  
Adaptor Protein ◽  
Dominant Negative ◽  
Mitogen Activated Protein Kinase ◽  
Hl60 Cells ◽  
Intracellular Signals ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Phosphoinositide 3 Kinase ◽  
Stimulation Of

Cell adhesion mediated by β1 integrin receptors leads to the initiation of intracellular signals that affect cell differentiation and survival. Here we have analysed the mechanism by which the α4β1 integrin activates the mitogen-activated protein kinase pathway in HL60 cells, a myelomonocytic cell line that lacks the expression of focal adhesion kinase. A role for phosphoinositide 3-kinase (PI-3K) in α4 integrin-mediated activation of extracellular signal-regulated protein kinase 2 (ERK2) is suggested by the ability of PI-3K inhibitors and a dominant-negative form of the p85 subunit of PI-3K to block the activation of ERK2 by integrin. Stimulation of α4β1 integrins on HL60 cells also leads to increased tyrosine phosphorylation of the 120 kDa adaptor protein Cbl. PI-3K activity associated with Cbl also increases on the stimulation of α4β1 integrins, although immunodepletion experiments suggest that Cbl-associated PI-3K does not account for all of the PI-3K activity induced on the stimulation of integrins in these cells. The expression of wild-type Cbl or the 70Z/3 Cbl mutant enhances basal ERK2 activity in transfectants with a minimal effect on α4 integrin-mediated ERK2 activity. In contrast, overexpression of the Hut Cbl truncation mutant, which does not associate with p85, has no effect on the ERK2 pathway. These results suggest that PI-3K has a major role in coupling α4β1 integrins to ERK2 activation in myeloid cells and that the Cbl adaptor protein has a role in basal, but not α4β1 integrin-mediated, activation of ERK2.

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