A kinase-independent function of AKT promotes cancer cell survival.
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Embargo End Date
ICR Authors
Authors
Vivanco, I
Chen, ZC
Tanos, B
Oldrini, B
Hsieh, W-Y
Yannuzzi, N
Campos, C
Mellinghoff, IK
Chen, ZC
Tanos, B
Oldrini, B
Hsieh, W-Y
Yannuzzi, N
Campos, C
Mellinghoff, IK
Document Type
Journal Article
Date
2014-12-31
Date Accepted
2014-12-31
Abstract
The serine-threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced 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.
Citation
eLife, 2014, 3
Source Title
Publisher
ELIFE SCIENCES PUBLICATIONS LTD
ISSN
2050-084X
eISSN
2050-084X
Collections
Research Team
Molecular Addictions