The NHE1 Na+/H+ Exchanger Recruits Ezrin/Radixin/Moesin Proteins to Regulate Akt-dependent Cell Survival

Autor: George Jarad, Martha Konieczkowski, Carlos A. Obejero-Paz, Amitava Mukherjee, Sujata Lakhe-Reddy, Jeffrey R. Schelling, Karen L. Wu, Shenaz Khan, John R. Sedor
Rok vydání: 2004
Předmět:
Sodium-Hydrogen Exchangers
Time Factors
Cell Survival
Moesin
Immunoblotting
Apoptosis
macromolecular substances
Protein Serine-Threonine Kinases
Biology
Transfection
Models
Biological
Biochemistry
Cell Line
Potassium Chloride
Phosphatidylinositol 3-Kinases
Cytosol
Ezrin
Radixin
Proto-Oncogene Proteins
Cell Adhesion
medicine
Humans
Staurosporine
Phosphorylation
Molecular Biology
Protein kinase B
Cytoskeleton
Dose-Response Relationship
Drug
Kinase
Microfilament Proteins
Membrane Proteins
Cortical actin cytoskeleton
Blood Proteins
Cell Biology
Hydrogen-Ion Concentration
Phosphoproteins
Precipitin Tests
Molecular biology
Up-Regulation
Cell biology
Cytoskeletal Proteins
Sodium–hydrogen antiporter
Ethylmaleimide
RNA Interference
Proto-Oncogene Proteins c-akt
Plasmids
Protein Binding
Signal Transduction
medicine.drug
Zdroj: Journal of Biological Chemistry. 279:26280-26286
ISSN: 0021-9258
DOI: 10.1074/jbc.m400814200
Popis: Apoptosis results in cell shrinkage and intracellular acidification, processes opposed by the ubiquitously expressed NHE1 Na(+)/H(+) exchanger. In addition to mediating Na(+)/H(+) transport, NHE1 interacts with ezrin/radixin/moesin (ERM), which tethers NHE1 to cortical actin cytoskeleton to regulate cell shape, adhesion, motility, and resistance to apoptosis. We hypothesize that apoptotic stress activates NHE1-dependent Na(+)/H(+) exchange, and NHE1-ERM interaction is required for cell survival signaling. Apoptotic stimuli induced NHE1-regulated Na(+)/H(+) transport, as demonstrated by ethyl-N-isopropyl-amiloride-inhibitable, intracellular alkalinization. Ectopic NHE1, but not NHE3, expression rescued NHE1-null cells from apoptosis induced by staurosporine or N-ethylmaleimide-stimulated KCl efflux. When cells were subjected to apoptotic stress, NHE1 and phosphorylated ERM physically associated within the cytoskeleton-enriched fraction, resulting in activation of the pro-survival kinase, Akt. NHE1-associated Akt activity and cell survival were inhibited in cells expressing ERM binding-deficient NHE1, dominant negative ezrin constructs, or ezrin mutants with defective binding to phosphoinositide 3-kinase, an upstream regulator of Akt. We conclude that NHE1 promotes cell survival by dual mechanisms: by defending cell volume and pH(i) through Na(+)/H(+) exchange and by functioning as a scaffold for recruitment of a signalplex that includes ERM, phosphoinositide 3-kinase, and Akt.
Databáze: OpenAIRE
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