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Regulation of local GTP availability controls RAC1 activity and cell invasion

Author

Listed:
  • Anna Bianchi-Smiraglia

    (Roswell Park Comprehensive Cancer Center)

  • David W. Wolff

    (Wake Forest University Baptist Medical Center)

  • Daniel J. Marston

    (University of North Carolina at Chapel Hill)

  • Zhiyong Deng

    (Wake Forest University Baptist Medical Center)

  • Zhannan Han

    (Wake Forest University Baptist Medical Center)

  • Sudha Moparthy

    (Wake Forest University Baptist Medical Center)

  • Rebecca M. Wombacher

    (Roswell Park Comprehensive Cancer Center)

  • Ashley L. Mussell

    (Roswell Park Comprehensive Cancer Center)

  • Shichen Shen

    (State University of New York at Buffalo)

  • Jialin Chen

    (Wake Forest University Baptist Medical Center)

  • Dong-Hyun Yun

    (Wake Forest University Baptist Medical Center)

  • Anderson O’Brien Cox

    (Wake Forest University Baptist Medical Center)

  • Cristina M. Furdui

    (Wake Forest University Baptist Medical Center)

  • Edward Hurley

    (Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo)

  • Maria Laura Feltri

    (Department of Biochemistry and Neurology, Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo)

  • Jun Qu

    (State University of New York at Buffalo)

  • Thomas Hollis

    (Wake Forest School of Medicine)

  • Jules Berlin Nde Kengne

    (University of Houston)

  • Bernard Fongang

    (University of Texas Health Science Center at San Antonio
    University of Texas Health Science Center at San Antonio)

  • Rui J. Sousa

    (University of Texas Health Science Center at San Antonio)

  • Mikhail E. Kandel

    (Groq, 400 Castro St #600)

  • Eugene S. Kandel

    (Roswell Park Comprehensive Cancer Center)

  • Klaus M. Hahn

    (University of North Carolina at Chapel Hill)

  • Mikhail A. Nikiforov

    (Wake Forest University Baptist Medical Center)

Abstract

Physiological changes in GTP levels in live cells have never been considered a regulatory step of RAC1 activation because intracellular GTP concentration (determined by chromatography or mass spectrometry) was shown to be substantially higher than the in vitro RAC1 GTP dissociation constant (RAC1-GTP Kd). Here, by combining genetically encoded GTP biosensors and a RAC1 activity biosensor, we demonstrated that GTP levels fluctuating around RAC1-GTP Kd correlated with changes in RAC1 activity in live cells. Furthermore, RAC1 co-localized in protrusions of invading cells with several guanylate metabolism enzymes, including rate-limiting inosine monophosphate dehydrogenase 2 (IMPDH2), which was partially due to direct RAC1-IMPDH2 interaction. Substitution of endogenous IMPDH2 with IMPDH2 mutants incapable of binding RAC1 did not affect total intracellular GTP levels but suppressed RAC1 activity. Targeting IMPDH2 away from the plasma membrane did not alter total intracellular GTP pools but decreased GTP levels in cell protrusions, RAC1 activity, and cell invasion. These data provide a mechanism of regulation of RAC1 activity by local GTP pools in live cells.

Suggested Citation

  • Anna Bianchi-Smiraglia & David W. Wolff & Daniel J. Marston & Zhiyong Deng & Zhannan Han & Sudha Moparthy & Rebecca M. Wombacher & Ashley L. Mussell & Shichen Shen & Jialin Chen & Dong-Hyun Yun & Ande, 2021. "Regulation of local GTP availability controls RAC1 activity and cell invasion," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26324-6
    DOI: 10.1038/s41467-021-26324-6
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    References listed on IDEAS

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    1. Matthias Machacek & Louis Hodgson & Christopher Welch & Hunter Elliott & Olivier Pertz & Perihan Nalbant & Amy Abell & Gary L. Johnson & Klaus M. Hahn & Gaudenz Danuser, 2009. "Coordination of Rho GTPase activities during cell protrusion," Nature, Nature, vol. 461(7260), pages 99-103, September.
    2. Madhusudhan Kollareddy & Elizabeth Dimitrova & Krishna C. Vallabhaneni & Adriano Chan & Thuc Le & Krishna M. Chauhan & Zunamys I. Carrero & Gopalakrishnan Ramakrishnan & Kounosuke Watabe & Ygal Haupt , 2015. "Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities," Nature Communications, Nature, vol. 6(1), pages 1-13, November.
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