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Molecular and Cellular Biology, November 2001, p. 7545-7557, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7545-7557.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Trophic Factor Withdrawal: p38 Mitogen-Activated Protein Kinase Activates NHE1, Which Induces Intracellular Alkalinization

Annette R. Khaled,1 Andrea N. Moor,2 Aiqun Li,3 Kyungjae Kim,1 Douglas K. Ferris,4 Kathrin Muegge,1 Robert J. Fisher,3 Larry Fliegel,2 and Scott K. Durum1,*

Laboratory of Molecular Immunoregulation,1 Intramural Research Support Program, SAIC Frederick,3 and Laboratory of Leukocyte Biology,4 Center for Cancer Research, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, and Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada2

Received 28 February 2001/Returned for modification 27 April 2001/Accepted 6 August 2001

Trophic factor withdrawal induces cell death by mechanisms that are incompletely understood. Previously we reported that withdrawal of interleukin-7 (IL-7) or IL-3 produced a rapid intracellular alkalinization, disrupting mitochondrial metabolism and activating the death protein Bax. We now observe that this novel alkalinization pathway is mediated by the pH regulator NHE1, as shown by the requirement for sodium, blocking by pharmacological inhibitors or use of an NHE1-deficient cell line, and the altered phosphorylation of NHE1. Alkalinization also required the stress-activated p38 mitogen-activated protein kinase (MAPK). Inhibition of p38 MAPK activity with pharmacological inhibitors or expression of a dominant negative kinase prevented alkalinization. Activated p38 MAPK directly phosphorylated the C terminus of NHE1 within a 40-amino-acid region. Analysis by mass spectroscopy identified four phosphorylation sites on NHE1, Thr 717, Ser 722, Ser 725, and Ser 728. Thus, loss of trophic cytokine signaling induced the p38 MAPK pathway, which phosphorylated NHE1 at specific sites, inducing intracellular alkalinization.

* Corresponding author. Mailing address: Section of Cytokines and Immunity, National Cancer Institute, Bldg. 560, Rm. 31-71, Frederick, MD 21702-1201. Phone: (301) 846-1545. Fax: (301) 846-6720. E-mail: durums{at}mail.ncifcrf.gov.

Molecular and Cellular Biology, November 2001, p. 7545-7557, Vol. 21, No. 22
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.22.7545-7557.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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