Mitogen-activated Protein Kinase-dependent Activation of the Na+/H+ Exchanger Is Mediated through Phosphorylation of Amino Acids Ser770 and Ser771

Malo, Mackenzie E.; Li, Liang; Fliegel, Larry

doi:10.1074/jbc.m611073200

Cited by 79 publications

(74 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…But, a role for intracellular acidosis in stimulation of NHE1 following in vivo cerebral ischemia cannot be ruled out. On the other hand, it has been reported that acidosis-mediated stimulation of NHE1 is not effective unless cultures are serum deprived previously (9). Our pure neuron cultures were maintained in the presence of B27 supplement.…”

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 98%

“…It has been suggested that ERK and p90 RSK can directly phosphorylate NHE1 at the distal C terminus phosphorylation domain and activate NHE1 in ischemic myocardium (8). Mutation of Ser 770 and Ser 771 in NHE1 abolishes ERK1/2-p90 RSK -mediated phosphorylation and activation of NHE1 following sustained intracellular acidosis (9). Serum stimulation of fibroblasts leads to phosphorylation of NHE1 and this phosphorylation is greatly diminished in the presence of the MEK1 inhibitor PD98059 (23).…”

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 99%

“…The distal C-terminal tail of NHE1 contains a number of serine and threonine residues that are phosphorylated by several protein kinases, including extracellular signal-related kinases (ERK1/2) and 90-kDa ribosomal S6 kinase (p90 RSK ) (8). Activation of the ERK/p90 RSK pathway is necessary for the increase in sarcolemmal NHE activity induced by myocardial ischemia and reperfusion (8) and sustained intracellular acidosis (9). However, it is unknown whether the ERK signaling cascade plays a role in regulation of NHE1 activity in neurons following in vitro ischemia.…”

mentioning

confidence: 99%

See 2 more Smart Citations

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Luo

Kintner

Shull

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

The function and regulation of Na ؉ /H ؉ exchanger isoform 1 (NHE1) following cerebral ischemia are not well understood. In this study, we demonstrate that extracellular signal-related kinases (ERK1/2) play a role in stimulation of neuronal NHE1 following in vitro ischemia. NHE1 activity was significantly increased during 10 -60 min reoxygenation (REOX) after 2-h oxygen and glucose deprivation (OGD). OGD/REOX not only increased the V max for NHE1 but also shifted the K m toward decreased [H ؉ ] i . These changes in NHE1 kinetics were absent when MAPK/ERK kinase (MEK) was inhibited by the MEK inhibitor U0126. There were no changes in the levels of phosphorylated ERK1/2 (p-ERK1/2) after 2 h OGD. The p-ERK1/2 level was significantly increased during 10 -60 min REOX, which was accompanied by nuclear translocation. U0126 abolished REOX-induced elevation and translocation of p-ERK1/2. We further examined the ERK/90-kDa ribosomal S6 kinase (p90 RSK ) signaling pathways. At 10 min REOX, phosphorylated NHE1 was increased with a concurrent elevation of phosphorylation of p90 RSK , a known NHE1 kinase. Inhibition of MEK activity with U0126 abolished phosphorylation of both NHE1 and p90 RSK . Moreover, neuroprotection was observed with U0126 or genetic ablation or pharmacological inhibition of NHE1 following OGD/REOX. Taken together, these results suggest that activation of ERK1/2-p90 RSK pathways following in vitro ischemia phosphorylates NHE1 and increases its activity, which subsequently contributes to neuronal damage. The Naϩ /H ϩ exchanger (NHE) 2 family is a group of membrane transport proteins that catalyzes the secondary active electroneurtral exchange of one Na ϩ for one H ϩ . To date, nine NHE isoforms (NHE1-9) have been cloned in mammalian tissues (1). Na ϩ /H ϩ exchanger isoform 1 (NHE1) is the most abundant NHE isoform in the rat central nervous system (2) and crucial in regulation of neuronal pH i (3, 4). We have recently reported that NHE1 activity plays an important role in neuronal damage in both in vitro and in vivo ischemic models (4). Inhibition of NHE1 activity during OGD/REOX prevents intracellular Na ϩ and Ca 2ϩ overload and thus reduces the Ca 2ϩ -mediated cascade of deleterious events (4). In acutely isolated CA1 neurons, an anoxia-triggered intracellular alkalization depends on activation of NHE1 (5). We also found that NHE1 activity is stimulated in cortical astrocytes following in vitro ischemia (6). However, whether NHE1 activity is overstimulated in cortical neurons following in vitro ischemia remains unknown.NHE1 has two large functional domains. The N-terminal transmembrane domain (ϳ500 amino acids) is responsible for cation translocation, and the cytoplasmic C-terminal domain (ϳ315 amino acids) is the main regulatory site for the NHE1 activity (7). The distal C-terminal tail of NHE1 contains a number of serine and threonine residues that are phosphorylated by several protein kinases, including extracellular signal-related kinases (ERK1/2) and 90-kDa ribosomal S6 kinase (p90 RSK ) (8). Activa...

show abstract

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 98%

Section: Nhe1 Activity Is Stimulated In Cortical Neurons Aftermentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Luo

Kintner

Shull

et al. 2007

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Examples of kinase-mediated activators of NHE1 include: extracellular signal regulated kinases ERK1/2 which are important in the activation of NHE1 in response to intracellular acidosis, and for which NHE1 serves as a signal scaffold (54,55); AKT (protein kinase B) which activates NHE1 in response to insulin and platelet-derived growth factor in fibroblasts (56), but inhibits NHE1 activity in cardiomyocytes (57); -Raf which phosphorylates NHE1 at amino acid threonine 653 (58); and p90 ribosomal S6 kinase (p90 RSK ) which phosphorylates NHE1 at serine 703, activating the exchanger in response to serum (59). Adaptor protein 14-3-3 binds NHE1 at the phosphorylated serine 703 residue and prevents its dephosphorylation (60).…”

Section: Nhe1: the Major Cellular Regulator Of Ph Homeostasismentioning

confidence: 99%

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

Amith

Fliegel

2017

Seminars in Cancer Biology

Self Cite

View full text Add to dashboard Cite

Please cite this article as: Amith Schammim Ray, Fliegel Larry.Na+/H+ exchangermediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics.Seminars in Cancer Biology http://dx.doi. org/10.1016/j.semcancer.2017.01.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Abstract (250 words):Breast cancer is the leading cause of cancer-related death in women in Europe and North America, and metastasis is the primary cause of fatality in patients with breast cancer. While some breast cancers are quite treatable, the triple-negative breast cancers are more metastatic and resistant to chemotherapy. There is clearly an urgent need for better treatments for this form of the disease. Breast cancer is characterized by genetically complex intra-tumour heterogeneity, particularly within the triple-negative clinical subtype. This complicates treatment options, so the development of specifically targeted chemotherapy for less treatable forms is critical.Dysregulation of pH homeostasis is a common factor in breast tumour cells. This occurs in concert with a metabolic switch to aerobic glycolysis that occurs at the onset of oncogenic transformation. The Na + /H + exchanger isoform 1 (NHE1) is the major pH regulatory protein involved in the increased proton extrusion of breast cancer cells. Its increased activity results in intracellular alkalinisation and extracellular acidification that drives cancer progression. The acidification of the extracellular tumour microenvironment also contributes to the development of chemotherapy resistance. In this review, we outline the role of H + as a carcinogenic signal and the role and regulation of NHE1 as a trigger for metastasis. We review recent evidence supporting the use of pharmacological inhibitors of NHE1 as a viable treatment option for triplenegative breast cancer.

show abstract

“…While in platelets and lymphocytes, NHE1 does not appear to be acutely regulated by vesicular insertion (Dixon et al, 1987), recent studies have demonstrated NHE1 plasma membrane translocation in response to integrin activation in fibroblasts (Yi et al, 2009) and insulin stimulation in cardiomyocytes (Lawrence et al, 2010), the latter in a PI3K-dependent manner. Both the PI3K-AKT and the MEK1/2-ERK1/2-p90 RSK signaling pathways have been implicated in the regulation of NHE1 activity, but the mechanisms involved are incompletely understood and conflicting evidence has been reported (Malo et al, 2007;Meima et al, 2009;Snabaitis et al, 2008;Takahashi et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways

Clement

Mally

Stock

et al. 2012

Journal of Cell Science

View full text Add to dashboard Cite

SummaryIn fibroblasts, platelet-derived growth factor receptor alpha (PDGFRa) is upregulated during growth arrest and compartmentalized to the primary cilium. PDGF-AA mediated activation of the dimerized ciliary receptor produces a phosphorylation cascade through the PI3K-AKT and MEK1/2-ERK1/2 pathways leading to the activation of the Na + /H + exchanger, NHE1, cytoplasmic alkalinization and actin nucleation at the lamellipodium that supports directional cell migration. We here show that AKT and MEK1/2-ERK1/2-p90 RSK inhibition reduced PDGF-AA-induced cell migration by distinct mechanisms: AKT inhibition reduced NHE1 activity by blocking the translocation of NHE1 to the cell membrane. MEK1/2 inhibition did not affect NHE1 activity but influenced NHE1 localization, causing NHE1 to localize discontinuously in patches along the plasma membrane, rather than preferentially at the lamellipodium. We also provide direct evidence of NHE1 translocation through the cytoplasm to the leading edge. In conclusion, signals initiated at the primary cilium through the PDGFRaa cascade reorganize the cytoskeleton to regulate cell migration differentially through the AKT and the MEK1/2-ERK1/2-p90 RSK pathways. The AKT pathway is necessary for initiation of NHE1 translocation, presumably in vesicles, to the leading edge and for its activation. In contrast, the MEK1/2-ERK1/2-p90 RSK pathway controls the spatial organization of NHE1 translocation and incorporation, and therefore specifies the direction of the leading edge formation.

show abstract

Mitogen-activated Protein Kinase-dependent Activation of the Na+/H+ Exchanger Is Mediated through Phosphorylation of Amino Acids Ser770 and Ser771

Cited by 79 publications

References 32 publications

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

ERK1/2-p90RSK-mediated Phosphorylation of Na+/H+ Exchanger Isoform 1

Na + /H + exchanger-mediated hydrogen ion extrusion as a carcinogenic signal in triple-negative breast cancer etiopathogenesis and prospects for its inhibition in therapeutics

PDGFRα signaling in the primary cilium regulates NHE1-dependent fibroblast migration via coordinated differential activity of MEK1/2-ERK1/2-p90RSK and AKT signaling pathways

Contact Info

Product

Resources

About