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Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK.

Many pro-apoptotic signals activate caspase-9, an initiator protease that activates caspase-3 and downstream caspases to initiate cellular destruction. However, survival signals can impinge on this pathway and suppress apoptosis. Activation of the Ras-Raf-MEK-ERK mitogen-activated protein kinase (MAPK) pathway is associated with protection of cells from apoptosis and inhibition of caspase-3 activation, although the targets are unknown. Here, we show that the ERK MAPK pathway inhibits caspase-9 activity by direct phosphorylation. In mammalian cell extracts, cytochrome c-induced activation of caspases-9 and -3 requires okadaic-acid-sensitive protein phosphatase activity. The opposing protein kinase activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2. Caspase-9 is phosphorylated at Thr 125, a conserved MAPK consensus site targeted by ERK2 in vitro, in a MEK-dependent manner in cells stimulated with epidermal growth factor (EGF) or 12-O-tetradecanoylphorbol-13-acetate (TPA). Phosphorylation at Thr 125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. We suggest that phosphorylation and inhibition of caspase-9 by ERK promotes cell survival during development and tissue homeostasis. This mechanism may also contribute to tumorigenesis when the ERK MAPK pathway is constitutively activated.

Pubmed ID: 12792650

Authors

  • Allan LA
  • Morrice N
  • Brady S
  • Magee G
  • Pathak S
  • Clarke PR

Journal

Nature cell biology

Publication Data

July 30, 2003

Associated Grants

None

Mesh Terms

  • 3T3 Cells
  • Animals
  • Apoptosis
  • Base Sequence
  • Caspase 3
  • Caspase 9
  • Caspases
  • Cell Survival
  • Cell Transformation, Neoplastic
  • Cytochrome c Group
  • Enzyme Inhibitors
  • Epidermal Growth Factor
  • Eukaryotic Cells
  • HeLa Cells
  • Humans
  • MAP Kinase Kinase 1
  • Mice
  • Mitogen-Activated Protein Kinase Kinases
  • Mitogen-Activated Protein Kinases
  • Molecular Sequence Data
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Pyridines
  • Recombinant Fusion Proteins
  • Signal Transduction
  • Threonine