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

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.

• Authors: Kate M Byrne, Naser Monsefi, John C Dawson, Andrea Degasperi, Jimi-Carlo Bukowski-Wills, Natalia Volinsky, Maciej Dobrzyński, Marc R Birtwistle, Mikhail A Tsyganov, Anatoly Kiyatkin, Katarzyna Kida, Andrew J Finch, Neil O Carragher, Walter Kolch, Lan K Nguyen, Alex von Kriegsheim, Boris N Kholodenko
• Journal: Cell systems (Cell Syst) Vol. 2 Issue 1 Pg. 38-48 (01 27 2016) ISSN: 2405-4712 [Print] United States
• PMID: 27136688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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