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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. |
Permanent link: | http://hdl.handle.net/10197/9760 | 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 inhibition; Rac1; RhoA; Bistable switches; Cell motility; Mathematical 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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