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Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway

Author

Listed:
  • Shigetoshi Yano

    (Vollum Institute, Oregon Health Sciences University)

  • Hiroshi Tokumitsu

    (Vollum Institute, Oregon Health Sciences University)

  • Thomas R. Soderling

    (Vollum Institute, Oregon Health Sciences University)

Abstract

The protection against apoptosis provided by growth factors in several cell lines is due to stimulation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, which results in activation of protein kinase B1,2 (PKB; also known as c-Akt and Rac) and phosphorylation and sequestration to protein 14-3-3 of the pro-apoptotic Bcl-2-family member BAD3,4,5,6,7. A modest increase in intracellular Ca2+ concentration also promotes survival of some cultured neurons8,9 through a pathway that requires calmodulin but is independent of PI(3)K and the MAP kinases10,11. Here we report that Ca2+/calmodulin-dependent protein kinase kinase (CaM-KK) activates PKB directly, resulting in phosphorylation of BAD on serine residue 136 and the interaction of BAD with protein 14-3-3. Serum withdrawal induced a three- to fourfold increase in cell death of NG108 neuroblastoma cells, and this apoptosis was largely blocked by increasing the intracellular Ca2+ concentration with NMDA (N-methyl-D-aspartate) or KCl or by transfection with constitutively active CaM-KK. The effect of NMDA on cell survival was blocked by transfection with dominant-negative forms of CaM-KK or PKB. These results identify a Ca2+-triggered signalling cascade in which CaM-KK activates PKB, which in turn phosphorylates BAD and protects cells from apoptosis.

Suggested Citation

  • Shigetoshi Yano & Hiroshi Tokumitsu & Thomas R. Soderling, 1998. "Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway," Nature, Nature, vol. 396(6711), pages 584-587, December.
    • Handle: RePEc:nat:nature:v:396:y:1998:i:6711:d:10.1038_25147
    DOI: 10.1038/25147
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    Cited by:

    1. Georgia Koppe & Anne Stephanie Mallien & Stefan Berger & Dusan Bartsch & Peter Gass & Barbara Vollmayr & Daniel Durstewitz, 2017. "CACNA1C gene regulates behavioral strategies in operant rule learning," PLOS Biology, Public Library of Science, vol. 15(6), pages 1-27, June.
    2. Liang Yong & Yafen Yu & Bao Li & Huiyao Ge & Qi Zhen & Yiwen Mao & Yanxia Yu & Lu Cao & Ruixue Zhang & Zhuo Li & Yirui Wang & Wencheng Fan & Chang Zhang & Daiyue Wang & Sihan Luo & Yuanming Bai & Shir, 2022. "Calcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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