Altering the threshold of an excitable signal transduction network changes cell migratory modes

Nat Cell Biol. 2017 Apr;19(4):329-340. doi: 10.1038/ncb3495. Epub 2017 Mar 27.

Abstract

The diverse migratory modes displayed by different cell types are generally believed to be idiosyncratic. Here we show that the migratory behaviour of Dictyostelium was switched from amoeboid to keratocyte-like and oscillatory modes by synthetically decreasing phosphatidylinositol-4,5-bisphosphate levels or increasing Ras/Rap-related activities. The perturbations at these key nodes of an excitable signal transduction network initiated a causal chain of events: the threshold for network activation was lowered, the speed and range of propagating waves of signal transduction activity increased, actin-driven cellular protrusions expanded and, consequently, the cell migratory mode transitions ensued. Conversely, innately keratocyte-like and oscillatory cells were promptly converted to amoeboid by inhibition of Ras effectors with restoration of directed migration. We use computational analysis to explain how thresholds control cell migration and discuss the architecture of the signal transduction network that gives rise to excitability.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Biosensing Techniques
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cell Movement* / drug effects
  • Cell Shape / drug effects
  • Computer Simulation
  • Cyclic AMP / pharmacology
  • Cytoskeleton / drug effects
  • Cytoskeleton / metabolism
  • Dictyostelium / cytology*
  • Dictyostelium / drug effects
  • Dictyostelium / metabolism*
  • Green Fluorescent Proteins / metabolism
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Signal Transduction* / drug effects
  • Time Factors
  • Time-Lapse Imaging

Substances

  • Actins
  • Phosphatidylinositol 4,5-Diphosphate
  • Green Fluorescent Proteins
  • Cyclic AMP