4.8 Article

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

出版社

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1809039115

关键词

signal transduction; phosphoinositides; chemotaxis; positive feedback loop; excitability

资金

  1. NIH [R35 GM118177, R01 GM089771, S10 OD016374, S10 OD023548]
  2. Air Force Office of Scientific Research Multidisciplinary University Research Initiative [FA95501610052]
  3. Defense Advanced Research Projects Agency [HR0011-16-C-0139]
  4. Office of the Provost of JHU
  5. U.S. Department of Defense (DOD) [FA95501610052] Funding Source: U.S. Department of Defense (DOD)

向作者/读者索取更多资源

Signal transduction and cytoskeleton networks in a wide variety of cells display excitability, but the mechanisms are poorly understood. Here, we show that during random migration and in response to chemoattractants, cells maintain complementary spatial and temporal distributions of Ras activity and phosphatidylinositol (3,4)-bisphosphate [PI(3,4)P-2]. In addition, depletion of PI(3,4)P-2 by disruption of the 5-phosphatase, Dd5P4, or by recruitment of 4-phosphatase INPP4B to the plasma membrane, leads to elevated Ras activity, cell spreading, and altered migratory behavior. Furthermore, RasGAP2 and RapGAP3 bind to PI(3,4)P-2, and the phenotypes of cells lacking these genes mimic those with low PI(3,4)P-2 levels, providing a molecular mechanism. These findings suggest that Ras activity drives PI(3,4)P-2 down, causing the PI(3,4)P-2-binding GAPs to dissociate from the membrane, further activating Ras, completing a positive-feedback loop essential for excitability. Consistently, a computational model incorporating such a feedback loop in an excitable network model accurately simulates the dynamic distributions of active Ras and PI(3,4)P-2 as well as cell migratory behavior. The mutually inhibitory Ras-PI(3,4)P-2 mechanisms we uncovered here provide a framework for Ras regulation that may play a key role in many physiological processes.

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