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Trophic factor withdrawal: p38 mitogen-activated protein kinase activates NHE1, which induces intracellular alkalinization

  1. Author:
    Khaled, A. R.
    Moor, A. N.
    Li, A. Q.
    Ferris, D. K.
    Muegge, K.
    Fisher, R. J.
    Fliegel, L.
    Durum, S. K.

  2. Author Address

    NCI, Sect Cytokines & Immun, Bldg 560, Rm 31-71, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, SAIC Frederick, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Leukocyte Biol, Ctr Canc Res, Frederick, MD 21702 USA. Univ Alberta, Dept Biochem, Edmonton, AB, Canada. Durum SK NCI, Sect Cytokines & Immun, Bldg 560, Rm 31-71, Frederick, MD 21702 USA.
    1. Year: 2001
  2. Journal: Molecular and Cellular Biology
    1. 21
    2. 22
    3. Pages: 7545-7557
  4. Type of Article: Article
  1. Abstract:

    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.

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