A kinase-independent function of AKT promotes cancer cell survival

  1. Igor Vivanco
  2. Zhi C Chen
  3. Barbara Tanos
  4. Barbara Oldrini
  5. Wan-Ying Hsieh
  6. Nicolas Yannuzzi
  7. Carl Campos
  8. Ingo K Mellinghoff  Is a corresponding author
  1. Memorial Sloan-Kettering Cancer Center, United States
  2. Spanish National Cancer Research Centre, Spain
  3. 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.

Article and author information

Author details

  1. Igor Vivanco

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zhi C Chen

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Barbara Tanos

    Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Barbara Oldrini

    Seve Ballesteros Foundation Brain Tumor Group, Spanish National Cancer Research Centre, Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  5. Wan-Ying Hsieh

    Department of Pharmacology, Weill-Cornell Graduate School of Biomedical Sciences, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Nicolas Yannuzzi

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Carl Campos

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Ingo K Mellinghoff

    Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, United States
    For correspondence
    mellingi@mskcc.org
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Roger Davis, University of Massachusetts Medical School, United States

Publication history

  1. Received: June 22, 2014
  2. Accepted: December 31, 2014
  3. Accepted Manuscript published: December 31, 2014 (version 1)
  4. 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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  1. Igor Vivanco
  2. Zhi C Chen
  3. Barbara Tanos
  4. Barbara Oldrini
  5. Wan-Ying Hsieh
  6. Nicolas Yannuzzi
  7. Carl Campos
  8. Ingo K Mellinghoff
(2014)
A kinase-independent function of AKT promotes cancer cell survival
eLife 3:e03751.
https://doi.org/10.7554/eLife.03751
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