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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
22
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pubmed:dateCreated |
2010-11-18
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pubmed:abstractText |
Activation of the cell-death mediator Bak commits a cell to mitochondrial apoptosis. The initial steps that govern Bak activation are poorly understood. To further clarify these pivotal events, we have investigated whether post-translational modifications of Bak impinge on its activation potential. In this study, we report that on apoptotic stimulation Bak undergoes dephosphorylation at tyrosine residue 108 (Y108), a critical event that is necessary but not sufficient for Bak activation, but is required both for early exposure of the occluded N-terminal domain and multimerisation. RNA interference (RNAi) screening identified non-receptor tyrosine phosphatases (PTPNs) required for Bak dephosphorylation and apoptotic induction through chemotherapeutic agents. Specifically, modulation of PTPN5 protein expression by siRNA and overexpression directly affected both Bak-Y108 phosphorylation and the initiation of Bak activation. We further show that MEK/ERK signalling directly affects Bak phosphorylation through inhibition of PTPN5 to promote cell survival. We propose a model of Bak activation in which the regulation of Bak dephosphorylation constitutes the initial step in the activation process, which reveals a previously unsuspected mechanism controlling the initiation of mitochondrial apoptosis.
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pubmed:grant |
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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 |
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pubmed:status |
MEDLINE
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pubmed:month |
Nov
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pubmed:issn |
1460-2075
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
17
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pubmed:volume |
29
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
3853-68
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pubmed:meshHeading |
pubmed-meshheading:20959805-Amino Acid Sequence,
pubmed-meshheading:20959805-Animals,
pubmed-meshheading:20959805-Apoptosis,
pubmed-meshheading:20959805-Cell Line,
pubmed-meshheading:20959805-Extracellular Signal-Regulated MAP Kinases,
pubmed-meshheading:20959805-Humans,
pubmed-meshheading:20959805-Mitochondria,
pubmed-meshheading:20959805-Molecular Sequence Data,
pubmed-meshheading:20959805-Phosphorylation,
pubmed-meshheading:20959805-Protein Tyrosine Phosphatases, Non-Receptor,
pubmed-meshheading:20959805-Serine,
pubmed-meshheading:20959805-Threonine,
pubmed-meshheading:20959805-Tyrosine,
pubmed-meshheading:20959805-bcl-2 Homologous Antagonist-Killer Protein
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pubmed:year |
2010
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pubmed:articleTitle |
Tyrosine dephosphorylation is required for Bak activation in apoptosis.
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pubmed:affiliation |
Department of Molecular Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, UK.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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