Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis

Abstract

Glutaminase (GLS) isoenzymes GLS1 and GLS2 are key enzymes for glutamine metabolism. Interestingly, GLS1 and GLS2 display contrasting functions in tumorigenesis with elusive mechanism; GLS1 promotes tumorigenesis, whereas GLS2 exhibits a tumor suppressive function. In this study, we found that GLS2 but not GLS1 binds to small GTPase Rac1 and inhibits its interaction with Rac1 activators guanine-nucleotide exchange factors (GEFs), which in turn inhibits Rac1 to suppress cancer metastasis. This function of GLS2 is independent of GLS2 glutaminase activity. Furthermore, decreased GLS2 expression is associated with enhanced metastasis in human cancer. As a p53 target, GLS2 mediates p53's function in metastasis suppression through inhibiting Rac1. In summary, our results reveal that GLS2 is a novel negative regulator of Rac1, and uncover a novel function and mechanism whereby GLS2 suppresses metastasis. Our results also elucidate a novel mechanism that contributes to the contrasting functions of GLS1 and GLS2 in tumorigenesis.

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Author details

  1. Cen Zhang

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Juan Liu

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Yuhan Zhao

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Xuetian Yue

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yu Zhu

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Xiaolong Wang

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Hao Wu

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Felix Blanco

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Shaohua Li

    Department of Surgery, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Gyan Bhanot

    Department of Molecular Biology, Biochemistry and Physics, Rutgers, The State University of New Jersey, Piscataway, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Bruce G Haffty

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Wenwei Hu

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Zhaohui Feng

    Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, United States
    For correspondence
    fengzh@cinj.rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (I12-002)of Rutgers, State University of New Jersey.

Copyright

© 2016, Zhang 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. Cen Zhang
  2. Juan Liu
  3. Yuhan Zhao
  4. Xuetian Yue
  5. Yu Zhu
  6. Xiaolong Wang
  7. Hao Wu
  8. Felix Blanco
  9. Shaohua Li
  10. Gyan Bhanot
  11. Bruce G Haffty
  12. Wenwei Hu
  13. Zhaohui Feng
(2016)
Glutaminase 2 is a novel negative regulator of small GTPase Rac1 and mediates p53 function in suppressing metastasis
eLife 5:e10727.
https://doi.org/10.7554/eLife.10727

Share this article

https://doi.org/10.7554/eLife.10727

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