A kinase-independent function of AKT promotes cancer cell survival

Igor Vivanco, Zhi C. Chen, Barbara Tanos, Barbara Oldrini, Wan Ying Hsieh, Nicolas Yannuzzi, Carl Campos, Ingo K. Mellinghoff

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

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.

Original languageEnglish (US)
Article numbere03751
JournaleLife
Volume3
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • AKT
  • cell biology
  • cell survival
  • human
  • human biology
  • kinase inhibitor
  • kinase-independent
  • medicine
  • mouse
  • oncogenic
  • PI3K

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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