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.
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
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
Nat. Cell Biol.
Date: Jul. 01, 2003
PubMed ID: 12792650
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