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rdf:type |
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lifeskim:mentions |
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0031715,
umls-concept:C0040005,
umls-concept:C0109317,
umls-concept:C0752312,
umls-concept:C0910167,
umls-concept:C1150579,
umls-concept:C1333340,
umls-concept:C1366882,
umls-concept:C1370600,
umls-concept:C1705767,
umls-concept:C1705791
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pubmed:issue |
7
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pubmed:dateCreated |
2003-6-30
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/CASP3 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/CASP9 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Casp3 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Casp9 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 3,
http://linkedlifedata.com/resource/pubmed/chemical/Caspase 9,
http://linkedlifedata.com/resource/pubmed/chemical/Caspases,
http://linkedlifedata.com/resource/pubmed/chemical/Cytochrome c Group,
http://linkedlifedata.com/resource/pubmed/chemical/Enzyme Inhibitors,
http://linkedlifedata.com/resource/pubmed/chemical/Epidermal Growth Factor,
http://linkedlifedata.com/resource/pubmed/chemical/MAP Kinase Kinase 1,
http://linkedlifedata.com/resource/pubmed/chemical/MAP2K1 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/Map2k1 protein, mouse,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinase...,
http://linkedlifedata.com/resource/pubmed/chemical/Mitogen-Activated Protein Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Protein-Serine-Threonine Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/Pyridines,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Threonine,
http://linkedlifedata.com/resource/pubmed/chemical/tris(2-pyridylmethyl)amine
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pubmed:status |
MEDLINE
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pubmed:month |
Jul
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pubmed:issn |
1465-7392
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
5
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
647-54
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:12792650-3T3 Cells,
pubmed-meshheading:12792650-Animals,
pubmed-meshheading:12792650-Apoptosis,
pubmed-meshheading:12792650-Base Sequence,
pubmed-meshheading:12792650-Caspase 3,
pubmed-meshheading:12792650-Caspase 9,
pubmed-meshheading:12792650-Caspases,
pubmed-meshheading:12792650-Cell Survival,
pubmed-meshheading:12792650-Cell Transformation, Neoplastic,
pubmed-meshheading:12792650-Cytochrome c Group,
pubmed-meshheading:12792650-Enzyme Inhibitors,
pubmed-meshheading:12792650-Epidermal Growth Factor,
pubmed-meshheading:12792650-Eukaryotic Cells,
pubmed-meshheading:12792650-HeLa Cells,
pubmed-meshheading:12792650-Humans,
pubmed-meshheading:12792650-MAP Kinase Kinase 1,
pubmed-meshheading:12792650-Mice,
pubmed-meshheading:12792650-Mitogen-Activated Protein Kinase Kinases,
pubmed-meshheading:12792650-Mitogen-Activated Protein Kinases,
pubmed-meshheading:12792650-Molecular Sequence Data,
pubmed-meshheading:12792650-Phosphorylation,
pubmed-meshheading:12792650-Protein-Serine-Threonine Kinases,
pubmed-meshheading:12792650-Pyridines,
pubmed-meshheading:12792650-Recombinant Fusion Proteins,
pubmed-meshheading:12792650-Signal Transduction,
pubmed-meshheading:12792650-Threonine
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pubmed:year |
2003
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pubmed:articleTitle |
Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK.
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pubmed:affiliation |
Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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