Caspase-activated phosphoinositide binding by CNT-1 promotes apoptosis by inhibiting the AKT pathway

Inactivation of cell survival factors is a crucial step in apoptosis. The phosphoinositide 3 kinase (PI3K) and 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 C. elegans, CNT-1, that upon cleavage by CED-3 during apoptosis activates an N-terminal phosphoinositide-binding fragment (tCNT-1), which translocates from cytoplasm to plasma membrane to block AKT binding to phosphatidylinositol (3,4,5)-triphosphate (PIP(3)), thereby disabling AKT activation and its pro-survival 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.