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

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Title: Bistability in the Rac1, PAK, and RhoA Signaling Network Drives Actin Cytoskeleton Dynamics and Cell Motility Switches
Authors: Byrne, Kate M.
Monsefi, Naser
Dawson, John C.
Degasperi, Andrea
Volinsky, Natalia
Dobrzyński, Maciej
Kida, Katarzyna
Kolch, Walter
Nguyen, Lan K.
Von Kriegsheim, Alex
Kholodenko, Boris N.
et al.
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Date: 27-Jan-2016
Online since: 2019-04-01T11:20:20Z
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.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Type of material: Journal Article
Publisher: Elsevier
Journal: Cell Systems
Volume: 2
Issue: 1
Start page: 38
End page: 48
Copyright (published version): 2016 the Authors
Keywords: PAK inhibitionRac1RhoABistable switchesCell motilityMathematical modeling
DOI: 10.1016/j.cels.2016.01.003
Language: en
Status of Item: Peer reviewed
Appears in Collections:Conway Institute Research Collection
SBI Research Collection
Medicine Research Collection

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