The NHE1 Na+/H+ exchanger recruits ezrin/radixin/moesin proteins to regulate Akt-dependent cell survival

Karen L. Wu, Shenaz Khan, Sujata Lakhe-Reddy, George Jarad, Amitava Mukherjee, Carlos A. Obejero-Paz, Martha Konieczkowski, John R. Sedor, Jeffrey R. Schelling

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134 Scopus citations

Abstract

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-Nisopropyl- amiloride-inhibitable, intracellular alkalinization. Ectopic NHE1, but not NHE3, expression rescued NHE1-null cells from apoptosis induced by staurosporine of 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 pHi through Na +/H+ exchange and by functioning as a scaffold for recruitment of a signalplex that includes ERM, phosphoinositide 3-kinase, and Akt.

Original languageEnglish
Pages (from-to)26280-26286
Number of pages7
JournalJournal of Biological Chemistry
Volume279
Issue number25
DOIs
StatePublished - Jun 18 2004
Externally publishedYes

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    Wu, K. L., Khan, S., Lakhe-Reddy, S., Jarad, G., Mukherjee, A., Obejero-Paz, C. A., Konieczkowski, M., Sedor, J. R., & Schelling, J. R. (2004). The NHE1 Na+/H+ exchanger recruits ezrin/radixin/moesin proteins to regulate Akt-dependent cell survival. Journal of Biological Chemistry, 279(25), 26280-26286. https://doi.org/10.1074/jbc.M400814200