AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin

Abstract

Loss of epithelial polarity impacts organ development and function; it is also oncogenic. AMPK, a key sensor of metabolic stress stabilizes cell-cell junctions and maintains epithelial polarity; its activation by Metformin protects the epithelial barrier against stress and suppresses tumorigenesis. How AMPK protects the epithelium remains unknown. Here we identify GIV/Girdin as a novel effector of AMPK, whose phosphorylation at a single site is both necessary and sufficient for strengthening mammalian epithelial tight junctions and preserving cell polarity and barrier function in the face of energetic stress. Expression of an oncogenic mutant of GIV (cataloged in TCGA) that cannot be phosphorylated by AMPK increased anchorage-independent growth of tumor cells and helped these cells evade the tumor-suppressive action of Metformin. This work defines a fundamental homeostatic mechanism by which the AMPK-GIV axis reinforces cell junctions against stress-induced collapse, and also provides mechanistic insight into the tumor-suppressive action of Metformin.

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Author details

  1. Nicolas Aznar

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Arjun Patel

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Cristina C Rohena

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Ying Dunkel

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Linda P Joosen

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Vanessa Taupin

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Irina Kufareva

    Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Marilyn G Farquhar

    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Pradipta Ghosh

    Department of Medicine, University of California, San Diego, La Jolla, United States
    For correspondence
    prghosh@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8917-3201

Funding

National Cancer Institute (R01CA100768)

  • Marilyn G Farquhar
  • Pradipta Ghosh

National Cancer Institute (R01CA160911)

  • Pradipta Ghosh

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK099226)

  • Pradipta Ghosh

American Cancer Society (ACS-IRG 70-002)

  • Pradipta Ghosh

National Cancer Institute (Postdoctoral FellowshipT32CA121938)

  • Cristina C Rohena

National Institute of General Medical Sciences (R01GM071872)

  • Irina Kufareva

National Institute of Allergy and Infectious Diseases (R01AI118985)

  • Irina Kufareva

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Johanna Ivaska, University of Turku, Finland

Publication history

  1. Received: August 21, 2016
  2. Accepted: November 3, 2016
  3. Accepted Manuscript published: November 4, 2016 (version 1)
  4. Version of Record published: November 22, 2016 (version 2)

Copyright

© 2016, Aznar 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. Nicolas Aznar
  2. Arjun Patel
  3. Cristina C Rohena
  4. Ying Dunkel
  5. Linda P Joosen
  6. Vanessa Taupin
  7. Irina Kufareva
  8. Marilyn G Farquhar
  9. Pradipta Ghosh
(2016)
AMP-activated protein kinase fortifies epithelial tight junctions during energetic stress via its effector GIV/Girdin
eLife 5:e20795.
https://doi.org/10.7554/eLife.20795

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