Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches

Cell Syst. 2016 Jan 27;2(1):38-48. doi: 10.1016/j.cels.2016.01.003. Epub 2016 Jan 27.

Abstract

Dynamic interactions between RhoA and Rac1, members of the Rho small GTPase family, play a vital role in the control of cell migration. Using predictive mathematical modeling, mass spectrometry-based quantitation of network components, and experimental validation in MDA-MB-231 mesenchymal breast cancer cells, we show that a network containing Rac1, RhoA, and PAK family kinases can produce bistable, switch-like responses to a graded PAK inhibition. Using a small chemical inhibitor of PAK, we demonstrate that cellular RhoA and Rac1 activation levels respond in a history-dependent, bistable manner to PAK inhibition. Consequently, we show that downstream signaling, actin dynamics, and cell migration also behave in a bistable fashion, displaying switches and hysteresis in response to PAK inhibition. Our results demonstrate that PAK is a critical component in the Rac1-RhoA inhibitory crosstalk that governs bistable GTPase activity, cell morphology, and cell migration switches.

Keywords: PAK inhibition; Rac1; RhoA; bistable switches; cell motility; mathematical modeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton*
  • Actins
  • Cell Line, Tumor
  • Cell Movement
  • Cytoskeleton
  • Humans
  • Protein Serine-Threonine Kinases
  • Signal Transduction
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein

Substances

  • Actins
  • Protein Serine-Threonine Kinases
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein