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

Kate m. Byrne, Naser Monsefi, John 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

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)38-48
JournalCell Systems
Volume2
Issue number1
Early online date27 Jan 2016
DOIs
Publication statusE-pub ahead of print - 27 Jan 2016

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