期刊
CELL DEATH AND DIFFERENTIATION
卷 16, 期 9, 页码 1215-1226出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2009.35
关键词
apoptosis; c-FLIP; phosphorylation; PKC; ubiquitylation
资金
- Academy of Finland
- Sigrid Juselius Foundation
- Research Institute of the Abo Akademi University
- Foundation of the Abo Akademi University
- Technical Development Agency of Finland (TEKES)
- Finnish Cancer Foundations
Cellular FLICE-inhibitory protein (c-FLIP) proteins are crucial regulators of the death-inducing signaling complex (DISC) and caspase-8 activation. To date, three c-FLIP isoforms with distinct functions and regulation have been identified. Our previous studies have shown that the stability of c-FLIP proteins is subject to isoform-specific regulation, but the underlying molecular mechanisms have not been known. Here, we identify serine 193 as a novel in vivo phosphorylation site of all c-FLIP proteins and demonstrate that S193 phosphorylation selectively influences the stability of the short c-FLIP isoforms, as S193D mutation inhibits the ubiquitylation and selectively prolongs the half-lives of c-FLIP short (c-FLIPS) and c-FLIP Raji (c-FLIPR). S193 phosphorylation also decreases the ubiquitylation of c-FLIP long (c-FLIPL) but, surprisingly, does not affect its stability, indicating that S193 phosphorylation has a different function in c-FLIPL. The phosphorylation of this residue is operated by the protein kinase C (PKC), as S193 phosphorylation is markedly increased by treatment with 12-O-tetradecanoylphorbol-13-acetate and decreased by inhibition of PKC alpha and PKC beta. S193 mutations do not affect the ability of c-FLIP to bind to the DISC, although S193 phosphorylation is increased by death receptor stimulation. Instead, S193 phosphorylation affects the intracellular level of c-FLIPS, which then determines the sensitivity to death-receptor-mediated apoptosis. These results reveal that the differential stability of c-FLIP proteins is regulated in an isoform-specific manner by PKC-mediated phosphorylation. Cell Death and Differentiation (2009) 16, 1215-1226; doi: 10.1038/cdd.2009.35; published online 3 April 2009
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