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.
Dawson, John C.
Nguyen, Lan K.
Von Kriegsheim, Alex
Kholodenko, Boris N.
|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|
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