A kinase-independent function of AKT promotes cancer cell survival
- Memorial Sloan-Kettering Cancer Center, United States
- Spanish National Cancer Research Centre, Spain
- Weill-Cornell Graduate School of Biomedical Sciences, United States
Abstract
The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. Here we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3-K), catalytically-inactive AKT (K179M) protected from druginduced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in-vitro and in AKT1/AKT2 double knockout cells, but promoted growth-factor independent survival of primary human melanocytes. ATP-competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer.
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© 2014, Vivanco et al.
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A kinase-independent function of AKT promotes cancer cell survival
eLife 3:e03751.
https://doi.org/10.7554/eLife.03751
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