Identification of PP1alpha as a caspase-9 regulator in IL-2 deprivation-induced apoptosis.
J Immunol
; 177(4): 2441-51, 2006 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-16888006
ABSTRACT
One of the mechanisms that regulate cell death is the reversible phosphorylation of proteins. ERK/MAPK phosphorylates caspase-9 at Thr(125), and this phosphorylation is crucial for caspase-9 inhibition. Until now, the phosphatase responsible for Thr(125) dephosphorylation has not been described. Here, we demonstrate that in IL-2-proliferating cells, phosphorylated serine/threonine phosphatase type 1alpha (PP1alpha) associates with phosphorylated caspase-9. IL-2 deprivation induces PP1alpha dephosphorylation, which leads to its activation and, as a consequence, dephosphorylation and activation of caspase-9 and subsequent dissociation of both molecules. In cell-free systems supplemented with ATP caspase-9 activation is induced by addition of cytochrome c and we show that in this process PP1alpha is indispensable for triggering caspase-9 as well as caspase-3 cleavage and activation. Moreover, PP1alpha associates with caspase-9 in vitro and in vivo, suggesting that it is the phosphatase responsible for caspase-9 dephosphorylation and activation. Finally, we describe two novel phosphatase-binding sites different from the previously described PP1alpha consensus motifs, and we demonstrate that these novel sites mediate the interaction of PP1alpha with caspase-9.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Interleucina-2
/
Apoptose
/
Fosfoproteínas Fosfatases
/
Caspases
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Immunol
Ano de publicação:
2006
Tipo de documento:
Article
País de afiliação:
França