The inhibition of AKT pathway by truncated CNT-1 enhances cell apoptosis


The phosphoinositide 3-kinase (PI3K)-AKT signaling pathway is crucial for promoting mammal cell growth, survival and proliferation. However, it reduces cell apoptosis and causes cancer. Nakagawa et al. demonstrated a new negative regulator of AKT signaling, truncated CNT-1 (tCNT-1), can promote cell apoptosis and suppress cell growth and proliferation. The article was published on Nature Structural & Molecular Biology.


The cell-suicide program is activated by caspases, a cysteine-aspartic proteases that cleave multiple substrates to mediate cell apoptosis. The Caenorhabditis elegans cell death protein, CED-3, is a caspase that is essential for cell death-execution process in C. elegans. Researchers found CNT-1 can be cut by CED-3 and produces tCNT-1, an N-terminal cleavage product. This product had strong phosphoinositide (PI)-binding affinity, therefore, it outcompeted AKT for binding to PIP3, inhibited PI3K-AKT pathway for enhancing cell apoptosis. By further investigation, researchers tested whether tCNT-1 can influence other functions of AKT kinases and PI3K, such as reducing life span and stress resistance in C. elegans. However, the absence of cnt-1 gene did not influence the two processes, which indicates tCNT-1 suppresses PI3K-AKT pathway in an apoptosis-specific manner.


Nat Struct Mol Biol. 2014 Nov 10;10.1038/nsmb.2915.

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