RRC ID 45813
Author Nakagawa A, Sullivan KD, Xue D.
Title Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway.
Journal Nat Struct Mol Biol
Abstract Inactivation of cell-survival factors is a crucial step in apoptosis. The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway promotes cell growth, proliferation and survival, and its deregulation causes cancer. How this pathway is suppressed to promote apoptosis is poorly understood. Here we report the identification of a CED-3 caspase substrate in Caenorhabditis elegans, CNT-1, that is cleaved during apoptosis to generate an N-terminal phosphoinositide-binding fragment (tCNT-1). tCNT-1 translocates from the cytoplasm to the plasma membrane and blocks AKT binding to phosphatidylinositol (3,4,5)-trisphosphate, thereby disabling AKT activation and its prosurvival activity. Our findings reveal a new mechanism that negatively regulates AKT cell signaling to promote apoptosis and that may restrict cell growth and proliferation in normal cells.
Volume 21(12)
Pages 1082-90
Published 2014-12-1
DOI 10.1038/nsmb.2915
PII nsmb.2915
PMID 25383666
PMC PMC4256149
MeSH Animals Apoptosis* Binding Sites Caenorhabditis elegans / chemistry Caenorhabditis elegans / cytology* Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / chemistry Caenorhabditis elegans Proteins / metabolism* Caspases / metabolism GTPase-Activating Proteins / chemistry GTPase-Activating Proteins / metabolism* Phosphatidylinositol 3-Kinases / metabolism Phosphatidylinositol Phosphates / metabolism Protein Binding Protein Transport Proto-Oncogene Proteins c-akt / metabolism* Signal Transduction*
IF 11.98
Times Cited 13
WOS Category BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
Resource
C.elegans tm2313 tm399 tm1075