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Activation of DAPK by PP2A mediates ceramide‐induced anoikis
Author(s) -
Widau Ryan Cole,
Jin Yijun,
Gallagher Patricia Jane
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1238.14
Subject(s) - ceramide , protein phosphatase 2 , dephosphorylation , microbiology and biotechnology , phosphorylation , anoikis , chemistry , phosphatase , apoptosis , sphingolipid , kinase , biology , programmed cell death , biochemistry
Ceramide is a pleiotrophic sphingolipid produced by cells in response to radiation, TNF, and chemotherapeutic drugs. Ceramide is a potent activator of protein phosphatases including PP2A leading to dephosphorylation of Bcl‐2 and Bax to result in mitochondrial dysfunction and apoptosis. Previous studies have demonstrated an important role for death associated protein kinase (DAPK), a Ca 2+ /calmodulin (CaM)‐regulated Ser/Thr kinase, in regulating ceramide‐induced apoptosis, through an unknown mechanism. The goals of these studies are to identify the S308 phosphatase involved in activation of DAPK and the mechanism by which DAPK mediates ceramide‐induced apoptosis. Tandem affinity purification (TAP) and MS identified PP2A as a potential phosphatase. Studies using siRNA‐mediated knockdown of the regulatory B subunit of PP2A resulted in increased phosphorylation of S308 and protein stability of DAPK in response to ceramide. These data suggest that activation of DAPK by PP2A, results in an overall decrease in rLC phosphorylation which is linked to depolymerization of actin cytoskeleton and cell detachment, resulting in apoptosis (anoikis). Ongoing studies are focused at elucidating the role of rLC phosphorylation and anoikis in response to ceramide. Supported by NCI‐CA11198, HL54118, and DK062810