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.
Article and author information
Author details
Reviewing Editor
- Roger Davis, University of Massachusetts Medical School, United States
Publication history
- Received: June 22, 2014
- Accepted: December 31, 2014
- Accepted Manuscript published: December 31, 2014 (version 1)
- Version of Record published: February 10, 2015 (version 2)
Copyright
© 2014, Vivanco et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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