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

Shigetoshi Yano, Hiroshi Tokumitsu, Thomas R. Soderling

Research output: Contribution to journalArticle

496 Citations (Scopus)

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 B (PKB; also known as c-Akt and Rac) and phosphorylation and sequestration to protein 14- 3-3 of the proapoptotic Bcl-2-family member BAD. A modest increase in intracellular Ca2+ concentration also promotes survival of some cultured neurons through a pathway that requires calmodulin but is independent of PI(3)K and the MAP kinases. 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.

Original languageEnglish
Pages (from-to)584-587
Number of pages4
JournalNature
Volume396
Issue number6711
DOIs
Publication statusPublished - Dec 10 1998
Externally publishedYes

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Proto-Oncogene Proteins c-akt
Calcium-Calmodulin-Dependent Protein Kinases
Cell Survival
Phosphotransferases
Phosphatidylinositol 3-Kinases
14-3-3 Proteins
Calcium
N-Methylaspartate
Apoptosis
Transfection
Phosphorylation
Mitogen-Activated Protein Kinase Kinases
Calmodulin
Neuroblastoma
Serine
Intercellular Signaling Peptides and Proteins
Cell Death
Neurons
Cell Line
Serum

ASJC Scopus subject areas

  • General

Cite this

Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. / Yano, Shigetoshi; Tokumitsu, Hiroshi; Soderling, Thomas R.

In: Nature, Vol. 396, No. 6711, 10.12.1998, p. 584-587.

Research output: Contribution to journalArticle

Yano, Shigetoshi ; Tokumitsu, Hiroshi ; Soderling, Thomas R. / Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. In: Nature. 1998 ; Vol. 396, No. 6711. pp. 584-587.
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