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Mutually inhibitory Ras-PI(3,4)P2 feedback loops mediate cell migration.

Xiaoguang Li1,2, Marc Edwards3, Kristen F Swaney4

  • 1Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205.

Proceedings of the National Academy of Sciences of the United States of America
|September 9, 2018
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Summary
This summary is machine-generated.

Cellular excitability involves a feedback loop between Ras activity and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2]. This mechanism regulates cell migration and may be crucial for various physiological processes.

Keywords:
chemotaxisexcitabilityphosphoinositidespositive feedback loopsignal transduction

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Area of Science:

  • Cellular signaling and motility
  • Molecular mechanisms of cell behavior

Background:

  • Cellular signal transduction and cytoskeleton networks exhibit excitability, but underlying mechanisms remain unclear.
  • Understanding these mechanisms is vital for comprehending cell migration and physiological processes.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing Ras activity and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P2] distributions in migrating cells.
  • To investigate the role of a Ras-PI(3,4)P2 feedback loop in cellular excitability and migratory behavior.

Main Methods:

  • Experimental manipulation of PI(3,4)P2 levels via phosphatase disruption (Dd5P4) and recruitment (INPP4B).
  • Analysis of Ras activity and cell migratory behavior under genetic and pharmacological perturbations.
  • Biochemical assays to determine RasGAP2 and RapGAP3 binding to PI(3,4)P2.
  • Computational modeling to simulate the dynamics of Ras-PI(3,4)P2 interactions and cell migration.

Main Results:

  • Cells maintain complementary spatial and temporal distributions of Ras activity and PI(3,4)P2 during migration.
  • Depletion of PI(3,4)P2 leads to increased Ras activity, enhanced cell spreading, and altered migration.
  • RasGAP2 and RapGAP3 bind to PI(3,4)P2, and their absence phenocopies low PI(3,4)P2 conditions.
  • A positive-feedback loop where Ras activity reduces PI(3,4)P2, releasing GAPs and further activating Ras, was identified.
  • Computational models accurately replicate observed dynamic distributions and migratory behaviors.

Conclusions:

  • A novel, mutually inhibitory feedback mechanism between Ras and PI(3,4)P2 is essential for cellular excitability.
  • This Ras-PI(3,4)P2 regulatory framework provides a molecular basis for understanding cell migration and signaling dynamics.
  • The discovered mechanism offers insights into broader physiological processes regulated by Ras signaling.